Author: "Centre d'Etude du Polymorphisme Humain (CEPH)" - Searchworks@Jio Institute Digital Library Search Results

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121 results on '"Centre d'Etude du Polymorphisme Humain (CEPH)"'

1. Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk

Author: Xavier Jouven, Beata Gyorgy, Pierre-Emmanuel Morange, Marie Germain, David M. Smadja, Noémie Saut, Marie-Christine Alessi, Pierre Suchon, Aurélien Delluc, Mona Ibrahim, David-Alexandre Trégouët, Jean-François Deleuze, Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Service d'hématologie biologique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Dpt Cardiologie [CHU Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL UPMC, Gestionnaire, Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Cavale Blanche, Service d'hématologie biologique [CHU Hôpital Européen Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Innovations thérapeutiques en hémostase ( IThEM - U1140 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset
Subjects: 0301 basic medicine, medicine.medical_specialty, Mutation, Missense, 030204 cardiovascular system & hematology, medicine.disease_cause, Gastroenterology, Risk Assessment, Protein S, Article, Loss of heterozygosity, 03 medical and health sciences, Plasma, 0302 clinical medicine, Polymorphism (computer science), [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Venous Thrombosis, Mutation, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, PROTEIN S HEERLEN, business.industry, medicine.disease, Quantitative determination, Surgery, Venous thrombosis, 030104 developmental biology, biology.protein, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Hereditary Protein S (PS) deficiency is a rare coagulation disorder associated with an increased risk of venous thrombosis (VT). The PS Heerlen (PSH) mutation is a rare S501P mutation that was initially considered to be a neutral polymorphism. However, it has been later shown that PSH has a reduced half-life in vivo which may explain the association of PSH heterozygosity with mildly reduced levels of plasma free PS (FPS). Whether the risk of VT is increased in PSH carriers remains unknown. We analyzed the association of PSH (rs121918472 A/G) with VT in 4,173 VT patients and 5,970 healthy individuals from four independent case-control studies. Quantitative determination of FPS levels was performed in a subsample of 1257 VT patients. In the investigated populations, the AG genotype was associated with an increased VT risk of 6.57 [4.06–10.64] (p = 1.73 10−14). In VT patients in whom PS deficiency was excluded, plasma FPS levels were significantly lower in individuals with PSH when compared to those without [72 + 13 vs 91 + 21 UI/dL; p = 1.86 10−6, mean + SD for PSH carriers (n = 21) or controls (n = 1236) respectively]. We provide strong evidence that the rare PSH variant is associated with VT in unselected individuals.
Published: 2017

2. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

Author: Marta Gut, Iris Pauporté, Cécile Mannina, Sancha Martin, Michael R. Stratton, Frédérique Penault-Llorca, Vincent Le Texier, Laurent Arnould, Pierre Saintigny, Marie-Christine Mathieu, P. Fumoleau, Xavier Pivot, Jean-François Deleuze, Hélène Blanché, Anthony Ferrari, Janice Kielbassa, Eskeatnaf Mulugeta, Olivier Tredan, Sandrine Boyault, Anne Vincent-Salomon, Thomas Bachelot, Emilie Thomas, Jean-Yves Pierga, Odette Mariani, Suzette Delaloge, Ivo Gut, Hervé Bonnefoi, Fabien Calvo, Frédéric Bibeau, Alain Viari, Serena Nik-Zainal, Anne-Sophie Sertier, Gilles Romieu, Maria Rios, Gaëtan MacGrogan, Jocelyne Jacquemier, Laurie Tonon, Gilles Thomas, Jean-Marc Ferrero, Isabelle Treilleux, Daniel Birnbaum, Catherine Bouteille, Carole Tarpin, Centre Léon Bérard [Lyon], Génétique et Biologie du Développement, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Gustave Roussy (IGR), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Ressources Biologiques [Paris], Institut Curie [Paris], Département de pathologie, Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Department of Medical Oncology [Lyon], UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, UNICANCER, Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Pôle de Chirurgie Oncologique générale, Gynécologique et Mammaire [Centre Antoine-Lacassagne], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chirurgie gynécologique, mammaire et réparatrice [Saint-Etienne], Clinique Mutualiste Chirurgicale [Saint-Étienne], Direction de la recherche [Gustave Roussy], Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), The Wellcome Trust Sanger Institute [Cambridge], Institut National du Cancer [Boulogne Billancourt] (INC), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Université de Franche-Comté ( UFC ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Institut Gustave Roussy ( IGR ), Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), Institut Curie, Institut Bergonié - CRLCC Bordeaux, Physico-Chimie-Curie ( PCC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut de Cancérologie de Lorraine - Alexis Vautrin ( ICL ), CRLCC Antoine Lacassagne, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université ( AMU ), Centre for Genomic Regulation [Barcelona] ( CRG ), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] ( CNAG ), Institut National du Cancer [Boulogne Billancourt] ( INC ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale ( ERABLE ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Nik-Zainal Abidin, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Sagot, Marie-France, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Institut Paoli Calmettes, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: 0301 basic medicine, DNA Copy Number Variations, Receptor, ErbB-2, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Breast Neoplasms, Biology, Genome, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Gene duplication, medicine, Humans, Copy-number variation, skin and connective tissue diseases, Genetics, Multidisciplinary, Whole Genome Sequencing, [ SDV ] Life Sciences [q-bio], Gene Expression Profiling, Estrogen Receptor alpha, Gene Amplification, General Chemistry, Amplicon, medicine.disease, 3. Good health, Gene expression profiling, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Human genome, Female, Receptors, Progesterone, Transcriptome
Abstract: HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal–basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage–fusion–bridge mechanism., Breast cancer is separated into multiple subtypes based on the expression of HER2 and hormone receptors. Here, the authors report the whole genome sequence of 64 HER2 positive tumours and show that these can be further separated into four groups with different gene expression profiles and genomic features.
Published: 2016

3. Excessive self-grooming of $Shank3$ mutant mice is associated with gene dysregulation and imbalance between the striosome and matrix compartments in the striatum

Author: Ferhat, Allain-Thibeault, Biton, Anne, Verpy, Elisabeth, Forget, Benoit, de Chaumont, Fabrice, Mueller, Florian, Le Sourd, Anne-Marie, Coqueran, Sabrina, Schmitt, Julien, Rochefort, Christelle, Rondi-Reig, Laure, Leboucher, Aziliz, Boland, Anne, Fin, Bertrand, Deleuze, Jean François, Boeckers, Tobias, Ey, Elodie, Bourgeron, Thomas, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Columbia University Medical Center (CUMC), Columbia University [New York], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation - Imaging and Modeling, Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CeZaMe - Cervelet, navigation et mémoire = Memory, Navigation and Aging (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Universität Ulm - Ulm University [Ulm, Allemagne], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-10-LABX-BioPsy, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Ey, Elodie, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, and Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID
Subjects: [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: Autism spectrum disorders (ASD) are characterised by atypical social communication and stereotyped behaviours. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1-2% of patients with ASD and intellectual disability (ID), but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterized the behaviour of Shank3 mutant mice deleted for exon 11 ( Shank3 $^{Δ11/Δ11}$ ) from three to twelve months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and atypical socio-sexual interaction compared to wild-type littermates. We then used RNAseq on four brain regions of the same animals to identify differentially expressed genes (DEG). DEGs were identified mainly in the striatum and were associated with synaptic transmission (e.g. Grm2 , Dlgap1 ), G-protein-signalling pathways (e.g. Gnal , Prkcg1 , and Camk2g ), as well as excitation/inhibition balance (e.g. Gad2 ). Downregulated and upregulated genes were respectively enriched in the gene clusters of medium-sized spiny neurons expressing the dopamine 1 (D1-MSN) and the dopamine 2 receptor (D2-MSN). Moreover, expression of DEGs reported as striosome markers within the striatum ( Cnr1 , Gnal1 , Gad2 , and Drd4 ) were positively correlated with excessive self-grooming. Finally, we showed that the striosome compartment of Shank3 Shank3 $^{Δ11/Δ11}$ mice was enlarged and displayed higher expression of GAD65 compared to wild-type mice. Altogether, these results shed light on a possible role of the striosomes/matrix imbalance in excessive self-grooming in Shank3Shank3 $^{Δ11/Δ11}$ mice. Such striatal alterations could be present in a subgroup of patients with ASD and ID and could open the way to new therapeutic approaches.
Published: 2022

4. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation

Author: Sylvie Salenave, Jessica Zucman-Rossi, Emmanuelle Jeannot, Gabrielle Couchy, Philippe Chanson, Paulette Bioulac-Sage, Jean-Charles Nault, Charles Balabaud, Marie-José Redon, Camilla Pilati, Sophie Prevot, Marie-Christine Saint-Paul, Philippe Labrune, Jeanne Tran Van Nhieu, Anne de Muret, Monique Fabre, Jean-Yves Scoazec, Catherine Buffet, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pôle Digestif, Hôpital Archet 2 [Nice] (CHU), Service d'hépato-gastro-entérologie, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et de Cytologie Pathologiques [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Antoine-Béclère, Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie [Béclère], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anipath, UFR Médecine Lyon-RTH Laennec-UFR Médecine Lyon-RTH Laennec, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service d'Endocrinologie et Maladies de la reproduction, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine-Béclère, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Anipath, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Hôpital Archet 2 [Nice] ( CHU ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine-Béclère, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Anipath, Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre
Subjects: Male, MESH: Signal Transduction, MESH : Liver Neoplasms, MESH : GTP-Binding Protein alpha Subunits, Gs, DNA Mutational Analysis, MESH : Aged, MESH : Models, Biological, Gene mutation, MESH: Base Sequence, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Adenoma, Liver Cell, 0302 clinical medicine, MESH: Liver Neoplasms, MESH : STAT3 Transcription Factor, GTP-Binding Protein alpha Subunits, Gs, MESH : Female, MESH: DNA Mutational Analysis, MESH: Carcinoma, Hepatocellular, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Liver Neoplasms, MESH: STAT3 Transcription Factor, DNA, Neoplasm, MESH : Adult, Middle Aged, 3. Good health, HNF1A, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Female, MESH : DNA, Neoplasm, MESH : Mutation, Signal Transduction, MESH : Carcinoma, Hepatocellular, Adult, STAT3 Transcription Factor, musculoskeletal diseases, Carcinoma, Hepatocellular, MESH: Mutation, MESH: Fibrous Dysplasia, Polyostotic, MESH : Male, MESH : Fibrous Dysplasia, Polyostotic, MESH: DNA, Neoplasm, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : DNA Mutational Analysis, Biology, Fibrous Dysplasia, Polyostotic, Models, Biological, Adenoma, Liver Cell, 03 medical and health sciences, MESH : Adenoma, Liver Cell, Chromogranins, medicine, GNAS complex locus, Humans, MESH : Middle Aged, Aged, 030304 developmental biology, MESH : Signal Transduction, MESH: Humans, Base Sequence, Hepatology, Oncogene, MESH : Humans, MESH: Models, Biological, MESH: Adult, Hepatocellular adenoma, MESH: GTP-Binding Protein alpha Subunits, Gs, medicine.disease, MESH: Male, Mutation, Inflammatory Hepatocellular Adenoma, biology.protein, Cancer research, MESH : Base Sequence, Carcinogenesis, MESH: Female
Abstract: Background & Aims Mosaic G-protein alpha-subunit ( GNAS )-activating mutations are responsible for the McCune–Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis. Methods GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines. Results A somatic GNAS -activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A , CTNNB1 , and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS -mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS -mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation. Conclusions We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS -activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.
Published: 2012

5. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Author: P. Bosco, Rebecca Sims, Monique M.B. Breteler, L. Concari, Giuseppe Tosto, María J. Bullido, Kristel Sleegers, Fernando Valdivieso, Diana Zelenika, T. Feulner, Raffaele Ferri, Christophe Tzourio, P. Caffara, Davide Seripa, Benjamin Grenier-Boley, Paola Bossù, C. Chillotti, Marc Delepine, C. Deniz-Naranjo, Daniela Galimberti, David-Alexandre Trégouët, Benedetta Nacmias, Elisabeth M. C. Schrijvers, Karolien Bettens, Anne Boland, Christiane Reitz, Florentino Sanchez-Garcia, Dominique Campion, R. Rogers, C. Van Broeckhoven, Jean-Charles Lambert, Denise Harold, Amy Gerrish, Didier Hannequin, Mohammad Arfan Ikram, Michael Conlon O'Donovan, Elio Scarpini, Giorgio Annoni, Vincent Chouraki, Marc Lathrop, Francesco Panza, Chandra A. Reynolds, Gabriele Siciliano, Sandro Sorbi, Philippe Amouyel, Florence Pasquier, Luc Buée, Mikko Hiltunen, Claudine Berr, Eliecer Coto, Victoria Alvarez, Caroline Graff, Vincenzo Solfrizzi, Julie Williams, Jonathan A. Prince, Martin Ingelsson, Michael John Owen, Laura Fratiglioni, Jennifer Chapman, Ignacio Mateo, Annick Alpérovitch, H. Soininen, Michelangelo Mancuso, G. Spalletta, Matthias Riemenschneider, Andrea Pilotto, C. Van Cauwenberghe, Jacques Epelbaum, M. Del Zompo, Onofre Combarros, Lars Lannfelt, Yoichiro Kamatani, Beatrice Arosio, Jean-François Dartigues, Inserm U744, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Cardiff University, Bioinformatics, GlaxoSmithKline, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium, University of Antwerp (UA), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Eastern Finland, G.H. Sergievsky Center, Columbia University, New York, NY, USA, Columbia University Irving Medical Center (CUIMC), Service of Neurology, University Hospital Marques de Valdecilla, University of Cantabria, Santander, Spain, Department of Psychiatry and Psychotherapy, Universitätsklinikum des Saarlandes, Universität des Saarlandes Saarbruecken, Germany, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Centro Dino Ferrari [Milano], Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Neuroscience, University of Parma, Parma, Italy, Università degli studi di Parma = University of Parma (UNIPR), Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central Asturias, Oviedo, Spain, Servicio de Inmunología. Hospital Unviersitario de Gran Canaria Dr Negrín. Bco, Las Palmas de Gran Canaria, Spain, Department of Geriatrics, Center for aging brain, Memory unit, University of Bari, Bari, Italy, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Department of neurological and psychiatric Sciences, University of Florence, Florence, Italy, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Roma, Italy, Clinical and Behavioral Neurology - Neuroscienze e riabilitazione, IRCCS Fondazione Santa Lucia [Roma], Neurological clinic, University of Pisa, Pisa, Italy, University of Pisa - Università di Pisa, Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden, KI-Alzheimer's Disease Reseach Center, Department NVS, Karolinska Institutet, KIADRC, Stockholm, Sweden, IRCCS Associazione Oasi Maria SS, Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy, Department of Psychology [Riverside], University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Uppsala University, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, Unit of Clinical Pharmacology, Teaching Hospital of Cagliari, Cagliari, Italy, Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, I.R.C.C.S. 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy, Università degli Studi di Cagliari = University of Cagliari (UniCa), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, DZNE, Bonn, Germany, Génomique cardiovasculaire, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation sur la recherche sur le cerveau) and Rotary., EADI consortium, GERAD consortium, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli studi di Bari Aldo Moro (UNIBA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut de psychiatrie et neurosciences (U894 / UMS 1266), University of California [Riverside] (UCR), University of California-University of California, Section of Clinical Pharmacology, Department of Neurosciences 'B.B. Brodie', University of Cagliari, Cagliari, Italy, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Lambert, J, Grenier Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K, Ikram, M, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, J, Tzourio, C, Berr, C, Schrijvers, E, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, C, Lannfelt, L, Ingelsson, M, Prince, J, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossù, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez Garcia, F, Del Zompo, M, Coto, E, Owen, M, O'Donovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buée, L, Campion, D, Soininen, H, Breteler, M, Riemenschneider, M, Van Broeckhoven, C, Alpérovitch, A, Lathrop, M, Trégouët, D, Williams, J, Amouyel, P, Epidemiology, Radiology & Nuclear Medicine, Neurology, Grenier-Boley, Benjamin, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé-Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Departement of Epidemiology and Radiology, Erasmus MC, Rotterdam, Centro de Biologia Molecular Severo Ochoa (UAM-CSIC) and CIBERNED, Universidad Autonoma, Madrid, Spain, Università degli studi di Milano [Milano]-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Internal Medicine, Geriatric Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy, University of Pisa [Pisa], Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Department of Epidemiology and Neurology, Erasmus MC, Rotterdam, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Aging Reasearch Center, Department NVS, Karolinska Institutet and Stockholm University, Stockholm, Sweden, University of California [Riverside] ( UCR ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Department of Epidemiology, Erasmus MC, Rotterdam, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]
Subjects: Apolipoprotein E, haplotype, FERM domain-containing protein 4A, human, genetics [Alzheimer Disease], Genome-wide association study, Disease, Genome, Plasma, 0302 clinical medicine, genetics [Adaptor Proteins, Signal Transducing], blood [Amyloid beta-Peptides], GWAS, genetics [Genetic Predisposition to Disease], [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics, 0303 health sciences, FRMD4A gene, amyloid, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, GWAS study, Alzheimer, FRMD4A, Alzheimer's disease, 3. Good health, Psychiatry and Mental health, Chemistry, genetics [Polymorphism, Single Nucleotide], Original Article, Corrigendum, medicine.medical_specialty, Amyloid, Single-nucleotide polymorphism, Locus (genetics), genome wide haplotype association study, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, blood [Alzheimer Disease], Alzheimer Disease, genetics [Haplotypes], Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Psychiatry, Molecular Biology, plasma, Genetic association, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Amyloid beta-Peptides, business.industry, Haplotype, Case-control study, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer’s disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case– control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P= 1.11010). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, P = 5.4107). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
Published: 2012

6. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Author: Bertolotto-Ballotti, Corine, Lesueur, Fabienne, Giuliano, Sandy, Strub, Thomas, de Lichy, Mahaut, Bille, Karine, Dessen, Philippe, d'Hayer, Benoit, Mohamdi, Hamida, Remenieras, Audrey, Maubec, Eve, de La Fouchardière, Arnaud, Molinié, Vincent, Vabres, Pierre, Dalle, Stéphane, Poulalhon, Nicolas, Martin-Denavit, Tanguy, Thomas, Luc, Andry-Benzaquen, Pascale, Dupin, Nicolas, Boitier, Françoise, Rossi, Annick, Perrot, Jean-Luc, Labeille, Bruno, Robert, Caroline, Escudier, Bernard, Caron, Olivier, Brugières, Laurence, Saule, Simon, Gardie, Betty, Gad, Sophie, Richard, Stéphane, Couturier, Jérôme, Teh, Bin Tean, Ghiorzo, Paola, Pastorino, Lorenza, Puig, Susana, Badenas, Celia, Olsson, Hakan, Ingvar, Christian, Rouleau, Etienne, Lidereau, Rosette, Bahadoran, Philippe, Vielh, Philippe, Corda, Eve, Blanché, Hélène, Zelenika, Diana, Galan, Pilar, Renseigné, Non, Aubin, François, Bachollet, Bertrand, Becuwe, Céline, Berthet, Pascaline, Bignon, yves Jean, Bonadona, Valérie, Bonafe, Jean-Louis, Bonnet-Dupeyron, Marie-Noëlle, Cambazard, Fréderic, Chevrant-Breton, Jacqueline, Coupier, Isabelle, Dalac, Sophie, Demange, Liliane, d'Incan, Michel, Dugast, Catherine, Faivre, Laurence, Vincent-Fétita, Lynda, Gauthier-Villars, Marion, Gilbert, Brigitte, Grange, Florent, Grob, Jean-Jacques, Humbert, Philippe, Janin, Nicolas, Joly, Pascal, Kerob, Delphine, Lasset, Christine, Leroux, Dominique, Levang, Julien, Limacher, Jean-Marc, Livideanu, Cristina, Longy, Michel, Lortholary, Alain, Stoppa-Lyonnet, Dominique, Mansard, Sandrine, Mansuy, Ludovic, Marrou, Karine, Matéus, Christine, Maugard, Christine, Meyer, Nicolas, Nogues, Catherine, Souteyrand, Pierre, Venat-Bouvet, Laurence, Zattara, Hélène, Chaudru, Valérie, Lenoir, Gilbert M, Lathrop, Mark, Davidson, Irwin, Avril, Marie-Françoise, Demenais, Florence, Ballotti, Robert, Bressac-de Paillerets, Brigitte, Biologie et pathologies des cellules mélanocytaires : de la pigmentation cutanée aux mélanomes, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), AxesSim, Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service de dermatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomopathologie [Fort de France, Martinique], CHU Fort de France, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Bases Moleculaires de l'Homeostasie Cutanee : Inflammation, Reparation et Cancer, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon, Parallel Cooperative Multi-criteria Optimization (DOLPHIN), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189 (CRIStAL), Ecole Centrale de Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Ecole Centrale de Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Valorisation Recherche et Innovations Alimentaire (Valorial), University Hospital of St-Etienne, Department of Dermatology, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'immunothérapie, Institut Gustave Roussy (IGR), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cytokines et Immunologie des Tumeurs Humaines (U753), Laboratoire de Génétique Oncologique [Villejuif], École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, Service de Génétique Oncologique, Institut Curie, Van Andel Research Institute, Grand Rapids, Michigan, Van Andel Institute [Grand Rapids], University of Barcelona, Hospital Clinic Barcelona, Lund University [Lund], Department of Surgery, Clinical Sciences, Genetique Moleculaire des Cancers d'Origine Epitheliale, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel - EA 3886), Université d'Évry-Val-d'Essonne (UEVE), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Cochin [AP-HP], Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditérannéen de médecine moléculaire (C3M), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Section Génétique - Groupe Prédispositions génétiques au cancer, Centre International de Recherche contre le Cancer (CIRC), Apoptose, cancer et immunité (U848), Département de dermatologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'anatomie pathologique, Hôpital Saint Joseph, Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Consultation de génétique, Département de Pédiatrie, Service de Pathologie, Institut Curie [Paris], Department of Oncology, Clinical Sciences, Department of Cancer Epidemiology, Clinical Sciences, Department of Surgery, University Hospital of Lund, Laboratoire d'Oncogénétique, CRLCC René Huguenin, Hôpital René HUGUENIN (Saint-Cloud), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de génétique Epidémiologique, Centre Léon Bérard [Lyon], CHU Saint-Etienne, Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Polyclinique de Courlancy, Service de Dermatologie, Hôtel-Dieu, CRLCC Eugène Marquis (CRLCC), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service de Genetique medicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM), Département de Génétique, CHU, Liège, Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Dermatology, Service d'onco-hématologie et génétique, CHU Grenoble, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de diagnostic génétique, Hôpital Universitaire de Strasbourg, Strasbourg, Laboratoire de biostatistique, CHU Strasbourg, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Département de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Functional Genomics and Cancer, Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Université Paris Diderot - Paris 7 (UPD7), We thank the patients and family members who participated in this study and the clinicians who identified these families, the French Familial Melanoma Study Group and the Inherited Predisposition to Kidney Cancer network. We acknowledge the contribution of the IGR Biobank for providing MELARISK samples and the CEPH Biobank for processing DNA samples. We thank L. Larue, J, Feunteun, A. Sarasin and E. Solary for critical reviews of the manuscript. We thank V. Lazar and S. Forget for coordination of the IGR's genomics and genetic platforms, N. Pata-Merci, V. Marty, S. Le Gras and A. Chabrier for their technical expertise, and M. Barrois for technical counselling. We also thank A. Boland for DNA extraction and quality control for genome-wide genotyping. This work was supported by grants from INSERM, Ligue Nationale Contre Le Cancer (PRE05/FD and PRE 09/FD) to F. D., Programme Hospitalier de Recherche Clinique (PHRC 2007/AOM-07-195) to M.-F.A. and F. D., ARC NoA09/5/5003 to B.B.-d.P., ARC 4985 to C. B., Institut National du Cancer (INCa)-Canceropole Ile de France (melanoma network RS#13) to B.B.-deP., INCa-PNES rein to B. G., S.Ga. and S. R., INCa grant R08009AP to C. B., Fondation de France 2010 to R. B., INCa and Ligue National Contre le Cancer to I. D., Fond de maturation IGR and Fondation Gustave Roussy to B.B.-d.P., Societe Francaise de Dermatologie SDF2004 to R. B. and P. B., SFD2009 to B.B.-d.P., 2009 SGR 1337 from AGAUR, Generalitat de Catalunya, and FIS PS09/01393 from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain to S. P. and C. B., and personal donations from C. and N. de Paillerets and M.-H.Wagner. to B.B.-d.P. B.B-d.P. holds an INSERM Research Fellowship for hospital-based scientists. Work at the Centre National de Genotypage (CNG) and Centre d'Etude du Polymorphisme Humain (CEPH) was supported in part by INCa., Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -IFR50-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique, Institut de cancérologie Gustave Roussy, Villejuif, France, Institut Gustave Roussy ( IGR ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques-Université de Franche-Comté ( UFC ), Laboratoire Electronique, Informatique et Image [UMR6303] ( Le2i ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-École Nationale Supérieure d'Arts et Métiers ( ENSAM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Cytokines et Immunologie des Tumeurs Humaines ( U753 ), INSTITUT CURIE, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC ), Centre François Baclesse, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, CRLCC Eugène Marquis ( CRLCC ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP), Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques-Université de Franche-Comté (UFC), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Arts et Métiers (ENSAM), HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: multidisciplinary sciences, MESH : Germ-Line Mutation, SUMO protein, urologic and male genital diseases, medicine.disease_cause, MESH : Neoplasm Invasiveness, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Carcinoma, Renal Cell, 0302 clinical medicine, Gene Frequency, Cell Movement, MESH: Germ-Line Mutation, MESH : Cell Movement, MESH : Gene Frequency, MESH: Cell Movement, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Multidisciplinary, MESH: Sumoylation, Melanoma, MESH : Sumoylation, MESH: Genetic Predisposition to Disease, renal carcinoma, MESH: Carcinoma, Renal Cell, Microphthalmia-associated transcription factor, MESH : Microphthalmia-Associated Transcription Factor, 3. Good health, germline mutation, 030220 oncology & carcinogenesis, MESH: Microphthalmia-Associated Transcription Factor, science and technology, MESH: Melanoma, sumo, MESH : Melanoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Germline mutation, melanoma, MESH: Gene Frequency, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Carcinoma, Renal Cell, neoplasms, Transcription factor, Germ-Line Mutation, 030304 developmental biology, Microphthalmia-Associated Transcription Factor, MESH: Humans, MESH : Humans, Sumoylation, MESH: Neoplasm Invasiveness, medicine.disease, HIF1A, cancer cells, Cancer research, MESH : Genetic Predisposition to Disease, Carcinogenesis
Abstract: International audience; So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
Published: 2011

7. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans

Author: Anais Grall, Céline Derbois, Matthieu Le Gallo, Ingrid Hausser, Laetitia Lagoutte, Sébastien Küry, Judith Fischer, Catherine André, Emmanuelle Bourrat, Emmanuel Bensignor, Sandrine Planchais, Franz P.W. Radner, Éric Guaguère, Francis Galibert, Rudolf Zechner, Susanne Grond, Jacques Fontaine, Robert Zimmermann, Gwang-Jin Kim, Mark Lathrop, Frédérique Degorce-Rubiales, Anne Thomas, Didier Pin, Christophe Hitte, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Clinique Vétérinaire Saint Bernard, Institute of Molecular Biosciences, Karl-Franzens-Universität Graz, Service de dermatologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of dermatology, University clinic Heidelberg, Electron Microscopy Core Facility, Universität Heidelberg [Heidelberg], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute for Human Genetics, University Clinic Freiburg, Faculty for Biology, University of Freiburg [Freiburg], Laboratoire d'Anatomie Pathologique Vétérinaire du Sud-Ouest, Animal Genetics Laboratory, Antagene, Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique Vétérinaire de la Boulais, Clinique vétérinaire, Clinique vétérinaire, Bruxelles, Interactions Cellules Environnement - UR (ICE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Zentrum für Biosystemanalyse, Albert-Ludwigs-Universität Freiburg, This study was supported by CNRS, the European Commission (FP7-LUPA, GA-201370). R. Zechner and R. Zimmermann were supported by the FWF F30 SFB Lipotox, Z136 Wittgenstein, the GEN-AU project GOLD by the Austrian Ministry of Science and Research and FFG. I.H. was supported by the NIRK Network (German BMBF 01GM0904)., European Project: 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA(2008), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Trousseau [APHP], Unité de Dermatologie, VetAgro Sup ( VAS ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, European Project : 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA ( 2008 ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Heidelberg [Heidelberg] = Heidelberg University, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), De Villemeur, Hervé, and Unravelling the molecular basis of common complex human disorders using the dog as a model system - LUPA - - EC:FP7:HEALTH2008-01-01 - 2012-06-30 - 201370 - VALID
Subjects: Male, MESH : Molecular Sequence Data, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Base Sequence, medicine.disease_cause, 0403 veterinary science, MESH: Dogs, MESH: INDEL Mutation, MESH: Lipase, MESH : Dogs, INDEL Mutation, Congenital ichthyosis, Missense mutation, MESH : Female, MESH: Animals, MESH: Codon, Nonsense, Cells, Cultured, Skin, Genetics, 0303 health sciences, Mutation, 04 agricultural and veterinary sciences, Lamellar ichthyosis, MESH : Adult, MESH : Lipase, MESH : Dermatologic Agents, MESH : Codon, Nonsense, MESH: Ichthyosis, Lamellar, Codon, Nonsense, Female, MESH : Genome-Wide Association Study, MESH: Cells, Cultured, Adult, 040301 veterinary sciences, MESH : Male, Nonsense mutation, Molecular Sequence Data, Mutation, Missense, ALOX12B, Golden Retriever, Genes, Recessive, MESH: Nitrendipine, Biology, 03 medical and health sciences, Dogs, MESH: Skin, MESH : Cells, Cultured, medicine, MESH : Skin, Animals, Humans, Indel, MESH : INDEL Mutation, MESH: Genes, Recessive, 030304 developmental biology, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Nitrendipine, MESH : Humans, MESH : Ichthyosis, Lamellar, MESH : Genes, Recessive, MESH: Adult, Lipase, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.disease, MESH : Nitrendipine, MESH: Male, MESH: Dermatologic Agents, MESH: Genome-Wide Association Study, MESH : Base Sequence, MESH : Animals, Dermatologic Agents, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, [ SDV.MHEP.DERM ] Life Sciences [q-bio]/Human health and pathology/Dermatology, MESH: Female, MESH : Mutation, Missense, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Ichthyosis, Lamellar, Genome-Wide Association Study
Abstract: International audience; Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.
Published: 2011

8. Publisher Correction: Heterogeneous SARS-CoV-2 humoral response after COVID-19 vaccination and/or infection in the general population

Author: Carrat, Fabrice, Villarroel, Paola Mariela Saba, Lapidus, Nathanael, Fourié, Toscane, Blanché, Hélène, Dorival, Céline, Nicol, Jérôme, Deleuze, Jean-François, Robineau, Olivier, Touvier, Mathilde, Severi, Gianluca, Zins, Marie, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Fondation Jean Dausset CEPH, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Università degli Studi di Firenze = University of Florence (UniFI), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), SAPRIS-SERO Study Group: Fabrice Carrat, Marie Zins, Gianluca Severi, Mathilde Touvier, Hélène Blanché, Jean-François Deleuze, Xavier de Lamballerie, Clovis Lusivika-Nzinga, Gregory Pannetier, Nathanael Lapidus, Isabelle Goderel, Céline Dorival, Jérôme Nicol, Olivier Robineau, Sofiane Kab, Adeline Renuy, Stéphane Le-Got, Céline Ribet, Mireille Pellicer, Emmanuel Wiernik, Marcel Goldberg, Fanny Artaud, Pascale Gerbouin-Rérolle, Mélody Enguix, Camille Laplanche, Roselyn Gomes-Rima, Lyan Hoang, Emmanuelle Correia, Alpha Amadou Barry, Nadège Senina, Julien Allegre, Fabien Szabo de Edelenyi, Nathalie Druesne-Pecollo, Younes Esseddik, Serge Hercberg, Mélanie Deschasaux, Hélène Blanché, Jean-Marc Sébaoun, Jean-Christophe Beaudoin, Laetitia Gressin, Valérie Morel, Ouissam Ouili, Jean-François Deleuze, Laetitia Ninove, Stéphane Priet, Paola Mariela Saba Villarroel, Toscane Fourié, Souand Mohamed Ali, Abdenour Amroun, Morgan Seston, Nazli Ayhan, Boris Pastorino, and CARRAT, FABRICE
Subjects: [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary
Abstract: International audience; No abstract available
Published: 2022

9. Heterogeneous SARS-CoV-2 humoral response after COVID-19 vaccination and/or infection in the general population

Author: Carrat, Fabrice, Saba Villarroel, Paola Mariela, Lapidus, Nathanaël, Fourié, Toscane, Blanché, Hélène, Dorival, Céline, Nicol, Jérôme, Deleuze, Jean-François, Robineau, Olivier, Touvier, Mathilde, Severi, Gianluca, Zins, Marie, de Lamballerie, Xavier, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), This study ANR (Agence Nationale de la Recherche, #ANR-20-COVI-000, #ANR-10-COHO-06), Fondation pour la Recherche Médicale (#20RR052-00), Inserm (Institut National de la Santé et de la Recherche Médicale, #C20-26). The sponsor and funders facilitated data acquisition but did not participate in the study design, analysis, interpretation or drafting. Cohorts funding The CONSTANCES Cohort Study is supported by the Caisse Nationale d’Assurance Maladie (CNAM), the French Ministry of Health, the Ministry of Research, the Institut national de la santé et de la recherche médicale. CONSTANCES benefits from a grant from the French National Research Agency [Grant Number ANR-11-INBS-0002] and is also partly funded by MSD, AstraZeneca, Lundbeck and L’Oreal. The E3N-E4N cohort is supported by the following institutions: Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation, INSERM, University Paris-Saclay, Gustave Roussy, the MGEN, and the French League Against Cancer. The NutriNet-Santé study is supported by the following public institutions: Ministère de la Santé, Santé Publique France, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRAE), Conservatoire National des Arts et Métiers (CNAM) and Sorbonne Paris Nord. The CEPH-Biobank is supported by the «Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation»., SAPRIS-SERO Study Group: Fabrice Carrat, Marie Zins, Gianluca Severi, Mathilde Touvier, Hélène Blanché, Jean-François Deleuze, Xavier de Lamballerie, Clovis Lusivika-Nzinga, Gregory Pannetier, Nathanael Lapidus, Isabelle Goderel, Céline Dorival, Jérôme Nicol, Olivier Robineau, Sofiane Kab, Adeline Renuy, Stéphane Le-Got, Céline Ribet, Mireille Pellicer, Emmanuel Wiernik, Marcel Goldberg, Fanny Artaud, Pascale Gerbouin-Rérolle, Mélody Enguix, Camille Laplanche, Roselyn Gomes-Rima, Lyan Hoang, Emmanuelle Correia, Alpha Amadou Barry, Nadège Senina, Julien Allegre, Fabien Szabo de Edelenyi, Nathalie Druesne-Pecollo, Younes Esseddik, Serge Hercberg, Mélanie Deschasaux, Hélène Blanché, Jean-Marc Sébaoun, Jean-Christophe Beaudoin, Laetitia Gressin, Valérie Morel, Ouissam Ouili, Jean-François Deleuze, Laetitia Ninove, Stéphane Priet, Paola Mariela Saba Villarroel, Toscane Fourié, Souand Mohamed Ali, Abdenour Amroun, Morgan Seston, Nazli Ayhan, Boris Pastorino, ANR-20-COVI-0038,COVID-METAFLAM,Mise en place d'une approche metabolomique ciblée à réponse rapide pour modéliser les cinétiques d'évolution des médiateurs de l'inflammation chez les patients COVID-19 au cours de leur prise en charge dans les services de réanimations.(2020), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), and Demarquay, Sandrine
Subjects: Adult, [SDV] Life Sciences [q-bio], COVID-19 Vaccines, Multidisciplinary, SARS-CoV-2, [SDV]Life Sciences [q-bio], Antibody Formation, Vaccination, COVID-19, Humans, Antibodies, Viral
Abstract: Assessment of the intensity, dynamics and determinants of the antibody response after SARS-CoV-2 infection or vaccination in the general population is critical to guide vaccination policies. This study characterized the anti-spike IgG titers in 13,971 participants included in a French multicohort population-based serological survey on COVID-19 between April and October 2020 and followed-up with serological testing between May and October 2021. Eight follow-up profiles were defined depending on SARS-CoV-2 infection (0, 1 or 2) and COVID-19 vaccination (0, 1, 2 or 3). The anti-spike titer was lower in adults with no vaccination even in case of infection or reinfection, while it was higher in adults with infection followed by vaccination. The anti-spike titer was negatively correlated with age in vaccinated but uninfected adults, whereas it was positively correlated with age in unvaccinated but infected adults. In adults with 2 vaccine injections and no infection, the vaccine protocol, age, gender, and time since the last vaccine injection were independently associated with the anti-spike titer. The decrease in anti-spike titer was much more rapid in vaccinated than in infected subjects. These results highlight the strong heterogeneity of the antibody response against SARS-CoV-2 in the general population depending on previous infection and vaccination.
Published: 2022

10. 17q21 variants modify the association between early respiratory infections and asthma

Author: Smit, L.A., Bouzigon, E., Pin, V., Siroux, V., Monier, F., Aschard, H., Bousquet, J., Gormand, F., Just, J., le Moual, N., Nadif, R., Scheinmann, P., Vervloet, D., Lathrop, M., Demenais, F., Kauffmann, F., Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, Faraldo, Beatrice, Programme Santé-environnement et Santé-travail - Facteurs environnementaux et interactions gène environnnement dans l'asthme et l'allergie - 2005 - ANR-05-SEST-0020 - SEST - VALID, Division of Environmental Epidemiology, Utrecht University [Utrecht]-Institute of Risk Assessment Sciences, Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pédiatrie, CHU Grenoble-Hôpital Michallon, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumo-Allergologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Supported by the French Ministry of Higher Education and Research, University Paris Diderot-Paris 7, grants from the French Agency for Environmental and Occupational Health Safety (grant AFSSET-APR-SE-2004), the French National Agency for Research (grants ANR 05-SEST-020-02/05-9-97 and ANR 06-CEBS), Merck Sharp & Dohme (MSD), Hospital program of clinical research (PHRC)-Paris, and GABRIEL, a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community (contract n° 01896 under the Integrated Programme LSH-2004-1.2.5-1 Post genomic approaches to understand the molecular bias of asthma aiming at a preventive or therapeutic control). Lidwien Smit is supported by a European Academy of Allergology and Clinical Immunology- Global Allergy and Asthma European Network (EAACI-GA2LEN) exchange fellowship award., ANR-05-SEST-0020,Facteurs environnementaux et interactions gène environnnement dans l'asthme et l'allergie(2005), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre de l'asthme et de l'allergologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), ANR-06-CEBS,ANR-06-CEBS, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS
Subjects: Male, MESH: Neoplasm Proteins, MESH : Retrospective Studies, MESH: Asthma, MESH : Respiratory Tract Infections, 0302 clinical medicine, MESH : Child, Risk Factors, immune system diseases, respiratory infection, MESH: Risk Factors, MESH: Child, Epidemiology, MESH : Female, Age of Onset, Young adult, Child, Respiratory Tract Infections, MESH: Genetic Association Studies, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Respiratory disease, ORMDL3, MESH: Genetic Predisposition to Disease, Respiratory infection, MESH : Chromosomes, Human, Pair 17, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Follow-Up Studies, MESH : Risk Factors, Neoplasm Proteins, MESH : Age of Onset, 3. Good health, MESH: Tobacco Smoke Pollution, Female, epidemiology, MESH: Membrane Proteins, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Adolescent, MESH : Male, MESH : Sex Factors, MESH: Age of Onset, Single-nucleotide polymorphism, MESH : Asthma, Polymorphism, Single Nucleotide, MESH : Tobacco Smoke Pollution, 03 medical and health sciences, Sex Factors, MESH : Neoplasm Proteins, MESH: Sex Factors, MESH : Adolescent, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Retrospective Studies, 030304 developmental biology, Asthma, Genetic association, MESH: Adolescent, MESH: Humans, business.industry, MESH : Humans, environmental tobacco smoke exposure, Membrane Proteins, MESH : Follow-Up Studies, MESH: Retrospective Studies, MESH : Genetic Association Studies, Odds ratio, medicine.disease, MESH: Male, respiratory tract diseases, gene-environment interaction, 030228 respiratory system, GSDML, MESH : Membrane Proteins, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Immunology, MESH: Respiratory Tract Infections, Tobacco Smoke Pollution, MESH : Genetic Predisposition to Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Chromosomes, Human, Pair 17, MESH: Female, Chromosomes, Human, Pair 17, Follow-Up Studies
Abstract: Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onsetor=4 yrs) were higher in carriers of risk genotypes (OR 3.42-6.36) than in noncarriers (OR 1.84-2.44; p-value for interaction 0.02-0.04 for five SNPs). Risk genotypes also increased the association between infection and childhood asthma that remits in adulthood (OR 4.84-7.16 in carriers and 1.74-2.25 in noncarriers; p-value for interaction 0.008-0.05 for 10 SNPs). In children with 17q21 risk genotypes and early-life environmental tobacco smoke (ETS) exposure, associations between infection and asthma were further enhanced. 17q21 genetic variants and early ETS exposure enhance the association between early respiratory infections and early-onset asthma and childhood asthma that remits in adulthood.
Published: 2010

11. Association of CYP1B1 Germ Line Mutations with Hepatocyte Nuclear Factor 1{alpha}-Mutated Hepatocellular Adenoma

Author: Emmanuelle Jeannot, Jean-Yves Scoazec, Nathalie Sturm, Laurence Chiche, Catherine Buffet, Christine Bellanné-Chantelot, Claudia de Toma, Yannick Bacq, Karine Poussin, Jessica Zucman-Rossi, Pierre Laurent-Puig, Paulette Bioulac-Sage, Jeanne Tran Van Nhieu, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Département de Chirurgie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de gastro-entérologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Pathologie Cellulaire, CHU Grenoble, Service d'hépato-gastro-entérologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was founded by the ARC grant n°5188, The Inserm 'Réseau de recherche clinique et en santé des populations', the SNFGE and the Fondation de France. EJ is recipient of an ARC fellowship., Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Service de chirurgie, CHU Caen, Service de gastro-entérologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de Cytogénétique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Zucman-Rossi, Jessica
Subjects: Cancer Research, Somatic cell, medicine.disease_cause, Germline, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Genotype, estrogen, Hepatocyte Nuclear Factor 1-alpha, tumor suppressor gene, Child, Genetics, Mutation, Liver Neoplasms, Middle Aged, 3. Good health, Pedigree, Oncology, 030220 oncology & carcinogenesis, Cytochrome P-450 CYP1B1, CYP1B1, 030211 gastroenterology & hepatology, Female, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Aryl Hydrocarbon Hydroxylases, Adult, endocrine system, Adenoma, Adolescent, cytochrome P450, hepatocellular adenoma, Biology, Adenoma, Liver Cell, 03 medical and health sciences, Germline mutation, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Alleles, Germ-Line Mutation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatocellular adenoma, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Mutagenesis, Site-Directed, mutation, genetic predisposition, metabolism
Abstract: Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1α (HNF1α) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1α germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1α-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1α-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1α-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1α mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line–inactivating mutations might increase the incidence of HCA in women with HNF1α mutations. [Cancer Res 2007;67(6):2611–6]
Published: 2007

12. Hepatocellular adenoma displaying a HNF1alpha inactivation in a patient with familial adenomatous polyposis coli

Author: François Paye, Najat Mourra, Dominique Wendum, Jean-François Fléjou, Claudia de Toma, Emmanuelle Jeannot, Jessica Zucman-Rossi, Zucman-Rossi, Jessica, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset
Subjects: Biallelic Mutation, MESH : Germ-Line Mutation, MESH : Immunohistochemistry, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Liv, Gene mutation, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH: Germ-Line Mutation, MESH : Female, MESH: Gene Silencing, Hepatocyte Nuclear Factor 1-alpha, MESH: Carcinoma, Hepatocellular, MESH: Liv, MESH: Genes, APC, biology, Reverse Transcriptase Polymerase Chain Reaction, Liver Neoplasms, Wnt signaling pathway, MESH: Genetic Predisposition to Disease, MESH : Adult, MESH : Diagnosis, Differential, Immunohistochemistry, 3. Good health, Adenomatous Polyposis Coli, 030220 oncology & carcinogenesis, Female, MESH : Hepatocyte Nuclear Factor 1-alpha, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030211 gastroenterology & hepatology, Adult, MESH : Carcinoma, Hepatocellular, congenital, hereditary, and neonatal diseases and abnormalities, Carcinoma, Hepatocellular, Genes, APC, Adenoma, Adenomatous polyposis coli, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, Diagnosis, Differential, 03 medical and health sciences, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Diagnosis, Differential, MESH : Gene Silencing, medicine, Humans, Genetic Predisposition to Disease, Gene Silencing, MESH: Hepatocyte Nuclear Factor 1-alpha, Alleles, Germ-Line Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Adenomatous Polyposis Coli, Hepatology, MESH: Alleles, MESH : Humans, MESH: Adult, MESH: Immunohistochemistry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatocellular adenoma, medicine.disease, MESH: Adenomatous Polyposis Coli, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Genes, APC, biology.protein, Cancer research, MESH : Genetic Predisposition to Disease, MESH : Alleles, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Carcinogenesis, MESH: Female
Abstract: Patients with familial adenomatous polyposis coli (FAP) may rarely develop hepatocellular adenoma. Here we report the case of a 37-year-old FAP woman presenting a hepatocellular adenoma after oestroprogestative oral contraception use. In this steatotic adenoma, we identified an inactivating biallelic mutation of HNF1alpha. In addition to the known germline APC mutation Q1062fs, we did not find an inactivation of the second APC allele nor an activation of the beta-catenin target genes GLUL and GPR49. Our findings contrast with two hepatocellular adenoma cases related to FAP, for which a biallelic inactivation of the APC gene was previously described. Altogether, these results suggest that benign hepatocellular carcinogenesis may be dependent on or independent of the Wnt/beta-catenin pathway in patients with FAP.
Published: 2006

13. Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia

Author: Youmna Ghaleb, Sandy Elbitar, Anne Philippi, Petra El Khoury, Yara Azar, Miangaly Andrianirina, Alexia Loste, Yara Abou-Khalil, Gaël Nicolas, Marie Le Borgne, Philippe Moulin, Mathilde Di-Filippo, Sybil Charrière, Michel Farnier, Cécile Yelnick, Valérie Carreau, Jean Ferrières, Jean-Michel Lecerf, Alexa Derksen, Geneviève Bernard, Marie-Soleil Gauthier, Benoit Coulombe, Dieter Lütjohann, Bertrand Fin, Anne Boland, Robert Olaso, Jean-François Deleuze, Jean-Pierre Rabès, Catherine Boileau, Marianne Abifadel, Mathilde Varret, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Université Saint-Joseph de Beyrouth (USJ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Epidémiologie et de Recherche en santé des POPulations (CERPOP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Réseau International des Instituts Pasteur (RIIP), McGill University Health Center [Montreal] (MUHC), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), McGill University = Université McGill [Montréal, Canada], University Hospital Bonn, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), PCSK9013, 13CVD03, ANR-10-LABX-0013, National Institutes of Health, NIH: BB-033-00065, R01 HL107816, Broad Institute, International Atherosclerosis Society, IAS, Canadian Institutes of Health Research, IRSC: 2017–2022, Fonds de Recherche du Québec - Santé, FRQS, Agence Nationale de la Recherche, ANR: ANR-16-RHUS-0007, Fondation Leducq, Institut National de la Santé et de la Recherche Médicale, Inserm, Conseil National de la Recherche Scientifique, CNRS, This work was supported by grants from the Leducq Foundation (FLQ # 13CVD03), the Laboratory of Excellence GENMED (Medical Genomics) grant no. ANR-10-LABX-0013 managed by the National Research Agency (ANR), part of the Investment for the Future program, and the National Project CHOPIN (Cholesterol Personalized Innovation) granted by the National Research Agency (ANR-16-RHUS-0007), INSERM (Institut National de la Sant? et de la Recherche M?dicale). Youmna Ghaleb is supported by a grant from the Lefoulon-Delalande Foundation and the International Atherosclerosis Society (IAS). Yara Azar and Yara Abou-Khalil are supported by grants from the Lebanese National Council for Scientific Research (CNRS-L) and the Council of Research of Saint-Joseph University of Beirut, Lebanon, Yara Azar is supported by a grant from AMGEN funding (PCSK9013). Yara Abou-Khalil is supported by a grant from Minist?re de l?Education Nationale et de la Technologie (France) and a grant from Nouvelle Soci?t? Francophone de l?Ath?roscl?rose (France). Genevi?ve Bernard received a Research Scholar Junior 1 award from the Fonds de Recherche du Qu?bec?Sant? (FRQS) (2012?2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017?2022). Acknowledgments: We thank all family members and the proband cohort for participating in the study. We thank Sekar Kathiresan, Gina Peloso and Nathan Stitziel (Broad Institute of MIT, Boston, MA, USA) for their help in the exome sequencing experiments. Sekar Kathiresan was supported by NIH R01 HL107816. We acknowledge the use of the bioresources of the Necker DNA Biobank (BB-033-00065). We thank Silvia Friedrichs for the technical assistance in sterol and bile acid analyses by GC-MS., Funding: This work was supported by grants from the Leducq Foundation (FLQ # 13CVD03), the Laboratory of Excellence GENMED (Medical Genomics) grant no. ANR-10-LABX-0013 managed by the National Research Agency (ANR), part of the Investment for the Future program, and the National Project CHOPIN (Cholesterol Personalized Innovation) granted by the National Research Agency (ANR-16-RHUS-0007), INSERM (Institut National de la Santé et de la Recherche Médicale). Youmna Ghaleb is supported by a grant from the Lefoulon-Delalande Foundation and the International Atherosclerosis Society (IAS). Yara Azar and Yara Abou-Khalil are supported by grants from the Lebanese National Council for Scientific Research (CNRS-L) and the Council of Research of Saint-Joseph University of Beirut, Lebanon, Yara Azar is supported by a grant from AMGEN funding (PCSK9013). Yara Abou-Khalil is supported by a grant from Ministère de l’Education Nationale et de la Technologie (France) and a grant from Nouvelle Société Francophone de l’Athérosclérose (France). Geneviève Bernard received a Research Scholar Junior 1 award from the Fonds de Recherche du Québec—Santé (FRQS) (2012–2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017–2022)., Acknowledgments: We thank all family members and the proband cohort for participating in the study. We thank Sekar Kathiresan, Gina Peloso and Nathan Stitziel (Broad Institute of MIT, Boston, MA, USA) for their help in the exome sequencing experiments. Sekar Kathiresan was supported by NIH R01 HL107816. We acknowledge the use of the bioresources of the Necker DNA Biobank (BB-033-00065). We thank Silvia Friedrichs for the technical assistance in sterol and bile acid analyses by GC-MS., HAL UVSQ, Équipe, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016)
Subjects: LRP6, CYP7A1, autosomal dominant hypercholesterolemia, oligogenic hypercholesterolemia, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, LDL uptake, Biochemistry, [SDV] Life Sciences [q-bio], LDLRAP1, polygenic risk score, linkage analysis, next-generation sequencing, Molecular Biology, protein structural models
Abstract: International audience; Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR, APOB, PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in CYP7A1, p.(Val1382Phe) in LRP6 and p.(Ser202His) in LDLRAP1. A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in CYP7A1; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in LRP6; and p.(Ser202LeufsTer19) in LDLRAP1. All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in CYP7A1 showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four LRP6 mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the LDLRAP1 p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype.
Published: 2022
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14. Operational tolerance after hematopoietic stem cell transplantation is characterized by distinct transcriptional, phenotypic, and metabolic signatures

Author: Laetitia Dubouchet, Helena Todorov, Ruth Seurinck, Nicolas Vallet, Sofie Van Gassen, Aurélien Corneau, Catherine Blanc, Habib Zouali, Anne Boland, Jean-François Deleuze, Brian Ingram, Regis Peffault de Latour, Yvan Saeys, Gérard Socié, David Michonneau, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Universiteit Gent = Ghent University (UGENT), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Metabolon INC, Hopital Saint-Louis [AP-HP] (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: EXPRESSION, IDENTIFICATION, [SDV]Life Sciences [q-bio], MATCHED UNRELATED DONORS, Hematopoietic Stem Cell Transplantation, Biology and Life Sciences, General Medicine, T REGULATORY CELLS, CHRONIC GVHD, KIDNEY, HLA Antigens, CYTOMETRY, THROMBOTIC MICROANGIOPATHY, B-CELLS, VERSUS-HOST-DISEASE, Immune Tolerance, Medicine and Health Sciences, Humans, Transplantation Tolerance
Abstract: The mechanisms underlying operational tolerance after hematopoietic stem cell transplantation in humans are poorly understood. We studied two independent cohorts of patients who underwent allogeneic hematopoietic stem cell transplantation from human leukocyte antigen–identical siblings. Primary tolerance was associated with long-lasting reshaping of the recipients’ immune system compared to their healthy donors with an increased proportion of regulatory T cell subsets and decreased T cell activation, proliferation, and migration. Transcriptomics profiles also identified a role for nicotinamide adenine dinucleotide biosynthesis in the regulation of immune cell functions. We then compared individuals with operational tolerance and nontolerant recipients at the phenotypic, transcriptomic, and metabolomic level. We observed alterations centered on CD38+-activated T and B cells in nontolerant patients. In tolerant patients, cell subsets with regulatory functions were prominent. RNA sequencing analyses highlighted modifications in the tolerant patients’ transcriptomic profiles, particularly with overexpression of the ectoenzymeNT5E(encoding CD73), which could counterbalance CD38 enzymatic functions by producing adenosine. Further, metabolomic analyses suggested a central role of androgens in establishing operational tolerance. These data were confirmed using an integrative approach to evaluating the immune landscape associated with operational tolerance. Thus, balance between a CD38-activated immune state and CD73-related production of adenosine may be a key regulator of operational tolerance.
Published: 2022

15. Persistent Symptoms After the First Wave of COVID-19 in Relation to SARS-CoV-2 Serology and Experience of Acute Symptoms: A Nested Survey in a Population-Based Cohort

Author: Olivier Robineau, Emmanuel Wiernik, Cédric Lemogne, Xavier de Lamballerie, Laetitia Ninove, Hélène Blanché, Jean-François Deleuze, Céline Ribet, Sofiane Kab, Marcel Goldberg, Gianluca Severi, Mathilde Touvier, Marie Zins, Fabrice Carrat, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier Gustave Dron [Tourcoing], Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The Constances cohort benefits from a grant from the French National Research Agency [Grant Number ANR-11-INBS-0002]: It is supported by the Caisse Nationale d'Assurance Maladie (CNAM), the French Ministry of Health, the Ministry of Research, the Institut national de la santé et de la recherche médicale. CONSTANCES and is also partly funded by MSD, AstraZeneca, Lundbeck and L'Oreal.The SAPRIS-SERO study was supported by Agence Nationale de la Recherche, #ANR-10-COHO-06, Santé Publique France: N°20DMIA014-0, Fondation pour la Recherche Médicale (#20RR052-00), Inserm (Institut National de la Santé et de la Recherche Médicale), #C20-26., ANR-11-INBS-0002,CONSTANCES,La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance(2011), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Demarquay, Sandrine, and Infrastructures - La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance - - CONSTANCES2011 - ANR-11-INBS-0002 - INBS - VALID
Subjects: Constances, Post-infectious symptoms, History, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Polymers and Plastics, [SDV]Life Sciences [q-bio], Health Policy, COVID-19, Persistent symptoms, Industrial and Manufacturing Engineering, [SDV] Life Sciences [q-bio], Populationbased study, Oncology, Long-covid, Post-covid condition, Internal Medicine, Business and International Management, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BackgroundMany patients report persistent symptoms after COVID-19. Our aim was to determine whether some of these symptoms were more associated with past SARS-CoV-2 infection compared to other conditions.MethodsThis prospective survey was nested in CONSTANCES, a randomly selected French population-based cohort, started in 2012. All participants being followed-up by internet completed 2 questionnaires during the first wave of the pandemic focusing on the acute symptoms of their COVID-19-like illness. Serological tests for SARS-CoV-2 were then performed (May-Nov 2020). Between December 2020 and January 2021, participants completed a third questionnaire about symptoms that had lasted more than 2 months. Participants were classified into four groups according to both European Center for Diseases Control (ECDC) criteria for COVID-19 (ECDC+ or ECDC-) and serological SARS-CoV-2 test results (Sero+ or Sero-). To compare the risk of each persistent symptom among the groups, logistic regression models were adjusted for age, sex, educational level, comorbidities, and the number of acute symptoms declared during the first wave of the epidemic. A mediation analysis was performed to estimate the direct effect of the infection on persistent symptoms and its indirect effect via the initial clinical presentation.FindingsThe analysis was performed in 25,910 participants. There was a higher risk of persistent dysgeusia/anosmia, dyspnea and asthenia in the ECDC+/Sero+ group than in the ECDC+/Sero- group (OR: 6.83 [4.47–10.42], 1.69 [1.07–2.6] and 1.48 [1.05–2.07], respectively). Abdominal pain, sensory symptoms or sleep disorders were at lower risk in the ECDC+/Sero+ group than in the ECDC+/Sero- group (0.51 [0.24–0.96], 0.40 [0.16–0.85], and 0.69 [0.49–0.95], respectively). The mediation analysis revealed that the association of the serological test results with each symptom was mainly mediated by ECDC symptoms (proportion mediated range 50–107%).ConclusionA greater risk of persistent dysgeusia/anosmia, dyspnea and asthenia was observed in SARS-CoV-2 infected people. The initial clinical presentation substantially drives the association of positive serological test results with persistent symptoms.
Published: 2022

16. Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families

Author: Isabella Annesi-Maesano, Francine Kauffmann, Marie-Pierre Oryszczyn, Evelyne Paty, Arnaud Lemainque, Emmanuelle Bouzigon, Marie-Hélène Dizier, Jean Bousquet, Frédéric Gormand, Nicole Le Moual, Florence Demenais, Jocelyne Just, Isabelle Pin, Denis Charpin, Françoise Neukirch, Christine Krähenbühl, Michel Guilloud-Bataille, Jean Maccario, Régis Matran, C Betard, Myriam Rosenberg-Bourgin, Daniel Vervloet, Mark Lathrop, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service Pneumologie – Allergologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital nord, Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Faculté des sciences pharmaceutiques et biologiques, Université Paris Descartes - Paris 5 (UPD5), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Département de pédiatrie, CHU Grenoble-Hôpital Michallon, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumo-Allergologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), E Bouzigon, MH Dizier, Just J, Le Moual N, Maccario J, R Matran, Neukirch F, MP Oryszczyn, E Paty, je Pin, M-Bourgin Rosenberg, Vervloet D, C Krähenbühl, Kauffmann F, Lathrop M, F Demenais ., Lemainque A, Annesi-Maesano I, C Betard, Bousquet J, Charpin D, F Gormand, Guilloud-Bataille M, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Assistance Publique - Hôpitaux de Marseille (APHM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Epidémiologie des maladies infectieuses et modélisation ( ESIM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hôpital nord, Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Génétique épidémiologique et structures des populations humaines ( Inserm U535 ), Epidémiologie, sciences sociales, santé publique ( IFR 69 ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École des hautes études en sciences sociales ( EHESS ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de l'asthme et de l'allergologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Paris Descartes - Paris 5 ( UPD5 ), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ), Centre de recherche en épidémiologie et santé des populations ( CESP ), and Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH: Asthma, Genetic Linkage, MESH: Genetic Markers, MESH : Microsatellite Repeats, Immunoglobulin E, Genome, MESH : Child, immune system diseases, MESH: Child, MESH : Genetic Markers, Child, Genetics (clinical), 0303 health sciences, biology, 030305 genetics & heredity, Smoking, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, General Medicine, respiratory system, Phenotype, 3. Good health, MESH : Smoking, MESH : Phenotype, France, MESH : Genome, Human, Genetic Markers, MESH: Smoking, Adolescent, MESH: Genetic Linkage, MESH : Asthma, MESH: Phenotype, 03 medical and health sciences, Genetic linkage, MESH : Adolescent, Genetics, medicine, Humans, MESH : France, Molecular Biology, MESH: Genome, Human, 030304 developmental biology, Asthma, MESH: Adolescent, MESH: Humans, Genome, Human, MESH : Humans, Total ige, medicine.disease, MESH : Genetic Linkage, MESH : Lod Score, respiratory tract diseases, MESH: France, MESH: Lod Score, Genetic marker, Immunology, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Microsatellite Repeats, Lod Score, Lod scores, Microsatellite Repeats
Abstract: A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P/=0.001): 6q14 for %FEV(1), 12p13 for IgE, 17q22-q24 for SPT and 21q21 for both SPTQ and %FEV(1). Nine other regions indicated smaller linkage signals (0.001P/=0.005). While most of these regions have been reported by previous asthma and lung function screens, 6q14 appears to be a new region potentially linked to %FEV(1). To determine which of these various asthma phenotypes are more likely to share common genetic determinants, a principal component analysis was applied to the genome-wide LOD scores. This analysis revealed clustering of LODs for asthma, SPT and Phadiatop on one axis and clustering of LODs for %FEV(1), BR and SPTQ on the other, while LODs for IgE and eosinophils appeared to be independent from all other LODs. These results provide new insights into the potential sharing of genetic determinants by asthma-related phenotypes.
Published: 2004

17. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Author: Magdalena Harakalova, Benjamin Meder, Philippe Charron, Manuel Gómez-Bueno, Jorg J. A. Calis, François Cambien, David-Alexandre Trégouët, Maurizia Grasso, Steven McGinn, Uwe Völker, Thomas Meitinger, Stefan Weiss, L. Duboscq-Bidot, Richard Dorent, Vera Regitz-Zagrosek, Folkert W. Asselbergs, Hélène Blanché, Olivier Dubourg, Patrick Lacolley, Pierre Boutouyrie, Delphine Bacq-Daian, Vincent Fontaine, Volker Ruppert, Marine Germain, K Lehnert, Jean-Noël Trochu, Stuart A. Cook, Angélique Curjol, Brendan J. Keating, Ibticem Raji, Anne Boland, J. Erdmann, Michael Morley, Jean-François Aupetit, Paloma Remior, Luigi Tavazzi, Gérard Roizès, Michal Mokry, Konstantin Strauch, Richard Isnard, Jean-Philippe Empana, Robert Olaso, Kenneth B. Marguiles, Zofia T. Bilińska, Stephan B. Felix, Marcus Dörr, Thomas P. Cappola, Stefan Blankenberg, Jan Haas, Céline Besse, Jean-François Deleuze, Christine E. Seidman, Christian Hengstenberg, Jessica van Setten, Hakon Hakonarson, Sanjay K Prasad, Daiane Hemerich, Pascal de Groote, Thomas Wichter, Alain van Mil, Michel Komajda, Renee Maas, Carole Proust, Declan P. O'Regan, Xavier Jouven, Ganapathi Varma Saripella, Georgios Kararigas, Eloisa Arbustini, Jin Li, Klaus Stark, Laurent Fauchier, Flavie Ader, Melanie Waldenberger, Martina Müller-Nurasyid, Eric Villard, Sophie Garnier, Cardiology, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique-Hôpitaux de Paris, Fondation Leducq, Société Française de Cardiologie, Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München, Université de Bordeaux, Medical Research Council, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University Medical Center [Utrecht], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Pennsylvania, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), National Heart Centre Singapore (NHCS), Children’s Hospital of Philadelphia (CHOP ), University of Regensburg, Royal Brompton Hospital, Imperial College London, Istituti Clinici Scientifici Maugeri [Pavia] (IRCCS Pavia - ICS Maugeri), Helmholtz Zentrum München = German Research Center for Environmental Health, Ludwig-Maximilians-Universität München (LMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University Medical Center of the Johannes Gutenberg-University Mainz, Perelman School of Medicine, Harvard Medical School [Boston] (HMS), University of Iceland [Reykjavik], Heidelberg University, Stanford University Medical School, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universität zu Lübeck = University of Lübeck [Lübeck], Universitätklinikum Gießen und Marburg GmbH, Maria Cecilia Hospital [Cotignola], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier Saint Joseph - Saint Luc [Lyon], National Institute of Cardiology [Varsovie, Pologne], University of Medicine Greifswald, Centre de Référence Maladies Cardiaques Héréditaires, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Swedish University of Agricultural Sciences (SLU), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Groupe Hospitalier Paris Saint Joseph, Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), and University College of London [London] (UCL)
Subjects: Cardiac & Cardiovascular Systems, Cardiomyopathy, Dilated/genetics, [SDV]Life Sciences [q-bio], Signal Transducing/genetics, Dilated cardiomyopathy, Genome-wide association study, Adaptor Proteins, Signal Transducing/genetics, 030204 cardiovascular system & hematology, TAURINE, 0302 clinical medicine, GWAS, Medicine, POSITION STATEMENT, 1102 Cardiorespiratory Medicine and Haematology, Genetics, 0303 health sciences, education.field_of_study, Genetic Predisposition to Disease/genetics, Adaptor Proteins, 4C-sequencing, Polymorphism, Single Nucleotide/genetics, Genetic risk score, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Single Nucleotide/genetics, Cardiomyopathy, Dilated, Cardiomyopathy, Population, Locus (genetics), Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Chromosomes, 03 medical and health sciences, Systolic/genetics, Heart Failure, Systolic/genetics, SNP, Animals, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, Imputation, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Heart Failure, Science & Technology, business.industry, WORKING GROUP, 1103 Clinical Sciences, medicine.disease, Genetic architecture, Cardiovascular System & Hematology, Dilated/genetics, Cardiovascular System & Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Apoptosis Regulatory Proteins, Heart Failure, Systolic, Genome-Wide Association Study
Abstract: Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
Published: 2021

18. Circadian genes polymorphisms, night work and prostate cancer risk: Findings from the EPICAP study

Author: Sylvie Cénée, Anne Boland, Florence Menegaux, Brigitte Trétarre, Pierre Laurent-Puig, Robert Olaso, Xavier Rebillard, Claire Mulot, Hélène Blanché, Pierre-Jean Lamy, Jean-François Deleuze, Thérèse Truong, Geraldine Cancel-Tassin, Olivier Cussenot, Méyomo G. Wendeu-Foyet, Yves Akoli Koudou, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Registre des tumeurs de l'Hérault, CRISAP-LR, COLRIM, EPC du CRLC-Centres privés de radiothérapie de l'Hérault-Laboratoires d'Hématologie CPAM - MSA - Caisse militaire, Clinique Beau Soleil [Montpellier], Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Service d'urologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Département de santé publique, Centre National de Recherche en Génomique Humaine [Évry] (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université de Paris (UP), Labosud, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, ANSES Ligue Contre le Cancer Fondation ARC pour la Recherche sur le Cancer, ARC Ligue Contre le Cancer Agence Française de Sécurité Sanitaire de l'Environnement et du Travail, AFSSET Institut National Du Cancer, INCa Fondation de France, We would like to thank the clinical research nurses who were in charge of participants’ interview, anthropometric measurements and biological sample collection (Anne‐Laure Astolfi, Coline Bernard, Oriane Boyer, Marie‐Hélène De Campo, Sandrine Margaroli, Louise N'Diaye, Sabine Perrier‐Bonnet). We also would like to thank Christian Prad and Nadine Soller for help with patient medical data collection within the Hérault Cancer Registry (Registre des tumeurs de l'Hérault, Montpellier, France) and Cécile Gaffory and Valérie Ondet for technical assistance (CeRePP). Finally, we are grateful to the EPICAP study Group: Urologists: Drs Didier Ayuso, Bruno Ségui, Vincent Abd El Fattah (Centre Hospitalier Bassin de Thau, Sète, France), Alain Guillaume, Jean‐Paul Constans, Olivier Delbos, Pierre Lanfray, Damien Rizet, Etienne Cuénant (Cabinet Urologie du Polygone, Montpellier, France), Michel Locci (Centre Hospitalier, Béziers, France), Etienne Cuénant (Clinique Ste Thérèse, Sète, France), Nicolas Drianno, Bernard Marc, Paulo Soares (Polyclinique Saint Privat, Béziers, France), Antoine Faix, Samer Abdel Hamid, Bruno Ségui (Service urologie, Clinique Beau Soleil, Montpellier, France), Samer Abdel Hamid (Clinique Saint Louis, Ganges, France), Thibaut Murez, Grégoire Poinas, Laurent Cabaniols, Maxime Robert, Rodolphe Thuret (Centre Hospitalo‐Universitaire, Hôpital Lapeyronie, Montpellier, France). Pathologists: Drs Didier Brel, Lysiane Schweizer, Philippe Nayraud, C. Lecam‐Savin (Inopath‐Biomed 34), Roland Daniel, Jean Baptiste Perdigou, Chantal Compan, Mireille Granier, Agnès Grranier, Ruth Borges‐Reis, Alena Badsi, Jean Louis Bouzigues, Elisabeth Broquerie (Inopath‐Labosud) Joëlle Simony, Frédéric Bibeau, Pierre Baldet, Isabelle Serre, Valérie Costes (Centre Hospitalo‐Universitaire, Hôpital Lapeyronie, Montpellier), Marie Laure Gaume (Sète). Biologists: Drs F. Montels (Service de Biologie Médicale, Institut du Cancer de Montpellier, Montpellier, France) and Labosud laboratories: Drs François et Pascal Dumas (Béziers, France), Martine Buono (Sète, France), Isabelle Bonnefille (Lodeve, France), Georges Ruiz (Lunel, France), Didier Paleirac (Clermont‐l'Hérault, France). The EPICAP‐chrono project was funded by Institut National du Cancer, Fondation ARC and Ligue nationale contre le cancer. The EPICAP study was funded by Ligue nationale contre le cancer, Ligue contre le cancer du Val de Marne, Fondation de France, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES). The first author has been granted by a Paris‐Sud University doctoral allowance., Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité)
Subjects: Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Genotyping Techniques, Population, interaction, Nerve Tissue Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, night work, Polymorphism, Single Nucleotide, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Circadian Clocks, Internal medicine, Basic Helix-Loop-Helix Transcription Factors, medicine, Humans, SNP, Genetic Predisposition to Disease, Circadian rhythm, education, Aged, education.field_of_study, NPAS2, business.industry, ARNTL Transcription Factors, Prostatic Neoplasms, Shift Work Schedule, Cancer, Nuclear Receptor Subfamily 1, Group F, Member 1, Odds ratio, Middle Aged, medicine.disease, prostate cancer, 3. Good health, pathway analysis, ARNTL, Logistic Models, Case-Control Studies, 030220 oncology & carcinogenesis, Neoplasm Grading, business, polymorphisms, circadian genes
Abstract: International audience; Over the past two decades, several studies have attempted to understand the hypothesis that disrupting the circadian rhythm may promote the development of cancer. Some have suggested that night work and some circadian genes polymorphisms are associated with cancer, including prostate cancer. Our study aims to test the hypothesis that prostate cancer risk among night workers may be modulated by genetic polymorphisms in the circadian pathway genes based on data from the EPICAP study, a population-based case-control study including 1511 men (732 cases/779 controls) with genotyped data. We estimated odds ratio (ORs) and P values of the association between prostate cancer and circadian gene variants using logistic regression models. We tested the interaction between circadian genes variants and night work indicators that were significantly associated with prostate cancer at pathway, gene and SNP levels. Analyses were also stratified by each of these night work indicators and by cancer aggressiveness. The circadian pathway was significantly associated with aggressive prostate cancer among night workers (P =.004), particularly for men who worked at night for 10 hours, P =.001). At the gene level, we observed among night workers significant associations between aggressive prostate cancer and ARNTL, NPAS2 and RORA. At the SNP-level, no significant association was observed. Our findings provide some clues of a potential modulating effect of circadian genes in the relationship between night work and prostate cancer. Further investigation is warranted to confirm these findings and to better elucidate the biological pathways involved.
Published: 2020

19. A novel rare c.-39C>T mutation in the PROS1 5'UTR causing PS deficiency by creating a new upstream translation initiation codone

Author: Labrouche-Colomer, Sylvie, Soukarieh, Omar, Proust, Carole, Mouton, Christine, Huguenin, Yoann, Roux, Maguelonne, Besse, Céline, Boland, Anne, Olaso, Robert, Constans, Joël, Deleuze, Jean-François, Morange, Pierre-Emmanuel, Jaspard-Vinassa, Béatrice, Trégouët, David-Alexandre, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'hématologie, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine, Institut de Génomique, CEA, Evry, France, Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was supported by the GENMED Laboratory of Excellence on Medical Genomics [grant number ANR-10-LABX-0013 (to O.S. and M.R.)], the «EPIDEMIOM-VTE» Senior Chair from the Initiative of Excellence of the University of Bordeaux [grant number ANR No.–10–IDEX-03-02 (to D.A.T.)], partially supported by the French Clinical Research Infrastructure Network on Venous Thrombo-Embolism (F-CRIN INNOVTE), and two research programs managed by the National Research Agency (ANR) as part of the French Investment for the Future., ANR-10-IDEX-0003,IDEX BORDEAUX,Initiative d'excellence de l'Université de Bordeaux(2010), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université de Paris (UP), Boullé, Christelle, Initiative d'excellence de l'Université de Bordeaux - - IDEX BORDEAUX2010 - ANR-10-IDEX-0003 - IDEX - VALID, and Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID
Subjects: Male, Base Sequence, Codon, Initiator, Pedigree, Protein S, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, open reading frame, Protein S deficiency, Young Adult, genomic medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, VINTAGE, Protein Biosynthesis, Humans, Female, Venos Thrombosis, mutation, 5' Untranslated Regions, HeLa Cells
Abstract: International audience; Autosomal dominant inherited Protein S deficiency (PSD) (MIM 612336) is a rare disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with seven PSD affected members in whom no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via an multiplex ligation-dependent probe amplification (MLPA) approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG→ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated in HeLa cells that the variant generates a novel overlapping upstream open reading frame (uORF) and inhibits the translation of the wild-type PS. This work describes the first example of 5'UTR PROS1 mutation causing PSD through the creation of an uORF, a mutation that is not predicted to be deleterious by standard annotation softwares, and emphasizes the need for better exploration of such type of non-coding variations in clinical genomics.
Published: 2020

20. Prediction of Breast Cancer Treatment-Induced Fatigue by Machine Learning Using Genome-Wide Association Data

Author: Paul Cottu, Anne-Laure Martin, Anne Boland, Cécile Charles, Jung Hun Oh, Marina Rousseau, Ines Vaz-Luis, Gwenn Menvielle, Joseph O. Deasy, Stefan Michiels, Céline Besse, Emilie Thomas, Jean-François Deleuze, Olivier Tredan, Patricia A. Ganz, Sandrine Boyault, Sibille Everhard, Fabrice Andre, Antonio Di Meglio, Ann H. Partridge, Agnès Dumas, Christelle Levy, Sangkyu Lee, Memorial Sloan Kettering Cancer Center (MSKCC), Institut Gustave Roussy (IGR), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Léon Bérard [Lyon], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Synergie Lyon Cancer [Lyon], Institut Curie [Paris], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), UNICANCER, University of California [Los Angeles] (UCLA), University of California (UC), Dana-Farber Cancer Institute [Boston], Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Synergie Lyon Cancer [Lyon], and Gestionnaire, Hal Sorbonne Université
Subjects: Cancer Research, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Genome-wide association study, Machine learning, computer.software_genre, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Clinical endpoint, 030304 developmental biology, 0303 health sciences, Surrogate endpoint, business.industry, Cancer, medicine.disease, [SDV] Life Sciences [q-bio], Oncology, Quartile, 030220 oncology & carcinogenesis, Anxiety, Artificial intelligence, medicine.symptom, business, computer
Abstract: Background We aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data. Methods We accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic (P Results Statistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association (P Conclusions Genomic analyses in this large cohort of breast cancer survivors suggest a possible genetic role for severe Cognitive Fatigue that warrants further exploration.
Published: 2019

21. Demethylation by low-dose 5-aza-2′-deoxycytidine impairs 3D melanoma invasion partially through miR-199a-3p expression revealing the role of this miR in melanoma

Author: Chantal Etievant, Audrey Delmas, Paola B. Arimondo, Arnaud Pillon, Gilles Favre, Joëlle Riond, Jörg Tost, Arnaud Carrier, Florence Busato, Cécile Desjobert, Antoine Daunay, Diego M. Marzese, Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoires Pierre Fabre, Laboratoire d'Epigénétique et d'Environnement [Evry] (CNG - CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de Genotypage-Institut de Génomique [Evry], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), John Wayne Cancer Institute [Santa Monica, CA, USA], Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported to P.B.A. by Centre National de la Recherche Scientifique (CNRS) [ATIP], Région Midi Pyrenées [Equipe d’Excellence and FEDER CNRS/Région Midi Pyrenées], Fondation InNaBioSanté, and PlanCancer2014 (N°EPIG201401)., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Riond, Joelle
Subjects: 0301 basic medicine, Lung Neoplasms, [SDV]Life Sciences [q-bio], lcsh:Medicine, MESH: Spheroids, Cellular, Transcriptome, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: DNA Methylation, MESH: Up-Regulation, MESH: Sequence Analysis, RNA, Gene Regulatory Networks, MESH: Animals, Promoter Regions, Genetic, Melanoma, Genetics (clinical), MESH: Gene Regulatory Networks, DNA methylation, microRNA, MESH: Gene Expression Regulation, Neoplastic, Up-Regulation, 3. Good health, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], MESH: Cell Survival, 030220 oncology & carcinogenesis, Female, Deoxycytidine, Epigenetics, MESH: Cell Line, Tumor, lcsh:QH426-470, Cell Survival, MESH: Melanoma, education, Biology, Decitabine, 03 medical and health sciences, MESH: Gene Expression Profiling, In vivo, Cell Line, Tumor, Spheroids, Cellular, MESH: Promoter Regions, Genetic, Genetics, medicine, Animals, Humans, Neoplasm Invasiveness, Molecular Biology, MESH: Mice, neoplasms, MESH: Humans, MESH: Decitabine, Sequence Analysis, RNA, Research, Gene Expression Profiling, lcsh:R, MESH: Neoplasm Invasiveness, medicine.disease, Demethylating agent, MESH: Lung Neoplasms, lcsh:Genetics, MicroRNAs, 030104 developmental biology, chemistry, Cancer research, Melanoma aggressiveness, MESH: Female, MESH: MicroRNAs, Neoplasm Transplantation, MESH: Neoplasm Transplantation, Developmental Biology
Abstract: Background Efficient treatments against metastatic melanoma dissemination are still lacking. Here, we report that low-cytotoxic concentrations of 5-aza-2′-deoxycytidine, a DNA demethylating agent, prevent in vitro 3D invasiveness of metastatic melanoma cells and reduce lung metastasis formation in vivo. Results We unravelled that this beneficial effect is in part due to MIR-199A2 re-expression by promoter demethylation. Alone, this miR showed an anti-invasive and anti-metastatic effect. Throughout integration of micro-RNA target prediction databases with transcriptomic analysis after 5-aza-2′-deoxycytidine treatments, we found that miR-199a-3p downregulates set of genes significantly involved in invasion/migration processes. In addition, analysis of data from melanoma patients showed a stage- and tissue type-dependent modulation of MIR-199A2 expression by DNA methylation. Conclusions Thus, our data suggest that epigenetic- and/or miR-based therapeutic strategies can be relevant to limit metastatic dissemination of melanoma. Electronic supplementary material The online version of this article (10.1186/s13148-018-0600-2) contains supplementary material, which is available to authorized users.
Published: 2019

22. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability

Author: Catherine Boileau, Anne Boland, Guillaume Jondeau, Mélodie Aubart, Jean-François Deleuze, Olivier Milleron, M. S. Gross, Steven Gazal, Nadine Hanna, Louise Benarroch, Marie-Paule Jacob, Emmanuelle Génin, Chantal Stheneur, Julien Buratti, Vincent Meyer, Thomas Bourgeron, Pauline Arnaud, Laurent Gouya, Isabelle Desguerre, Habib Zouali, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and Benarroch, Louise
Subjects: Adult, Collagen Type IV, Male, 0301 basic medicine, Marfan syndrome, Multifactorial Inheritance, Adolescent, Genetic Linkage, Fibrillin-1, [SDV]Life Sciences [q-bio], Quantitative Trait Loci, 030204 cardiovascular system & hematology, Biology, Thoracic aortic aneurysm, Article, Marfan Syndrome, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Genotype, Genetics, medicine, Humans, Cells, Cultured, Genetics (clinical), Exome sequencing, Aged, Genes, Modifier, Fibroblasts, Middle Aged, medicine.disease, Genetic architecture, [SDV] Life Sciences [q-bio], Phenotype, 030104 developmental biology, Mutation, Expression quantitative trait loci, Female, Age of onset
Abstract: International audience; Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.
Published: 2018

23. OPTIMIR, a novel algorithm for integrating available genome-wide genotype data into miRNA sequence alignment analysis

Author: Florian Thibord, Pierre Suchon, Pierre-Emmanuel Morange, David-Alexandre Trégouët, Maguelonne Roux, Claire Perret, Marine Germain, Jean-François Deleuze, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre recherche en CardioVasculaire et Nutrition (C2VN), and Gestionnaire, Hal Sorbonne Université
Subjects: Heterozygote, Genotype, Bioinformatics, Computer science, [SDV]Life Sciences [q-bio], Sequence alignment, Genome, 03 medical and health sciences, 0302 clinical medicine, isomiRs, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Databases, Genetic, Genetic variation, microRNA, Humans, Genotyping, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, computer.programming_language, Venous Thrombosis, 0303 health sciences, Base Sequence, Genome, Human, Computational Biology, alignment, Python (programming language), [SDV] Life Sciences [q-bio], MicroRNAs, Allelic Imbalance, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], next-generation sequencing, genetic variations, Sequence Alignment, computer, Algorithm, Algorithms, Software, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Next-generation sequencing is an increasingly popular and efficient approach to characterize the full set of microRNAs (miRNAs) present in human biosamples. MiRNAs’ detection and quantification still remain a challenge as they can undergo different post transcriptional modifications and might harbor genetic variations (polymiRs) that may impact on the alignment step. We present a novel algorithm, OPTIMIR, that incorporates biological knowledge on miRNA editing and genome-wide genotype data available in the processed samples to improve alignment accuracy.OPTIMIR was applied to 391 human plasma samples that had been typed with genome-wide genotyping arrays. OPTIMIR was able to detect genotyping errors, suggested the existence of novel miRNAs and highlighted the allelic imbalance expression of polymiRs in heterozygous carriers.OPTIMIR is written in python, and freely available on the GENMED website (http://www.genmed.fr/index.php/fr/) and on Github (github.com/FlorianThibord/OptimiR).
Published: 2019

24. Clustering and variable selection evaluation of 13 unsupervised methods for multi-omics data integration

Author: Jean-François Deleuze, Edith Le Floch, Morgane Pierre-Jean, Florence Mauger, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Computer science, Feature selection, computer.software_genre, Matrix decomposition, unsupervised integrative methods, 03 medical and health sciences, 0302 clinical medicine, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Neoplasms, benchmarks, Cluster Analysis, Humans, Computer Simulation, Cluster analysis, Molecular Biology, 030304 developmental biology, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], Massive parallel sequencing, Computational Biology, Genomics, multi-omics, Omics, performance evaluation, 030220 oncology & carcinogenesis, Generalized canonical correlation, Multivariate Analysis, Data mining, Canonical correlation, computer, Algorithms, real data, Information Systems, Data integration
Abstract: Recent advances in NGS sequencing, microarrays and mass spectrometry for omics data production have enabled the generation and collection of different modalities of high-dimensional molecular data. The integration of multiple omics datasets is a statistical challenge, due to the limited number of individuals, the high number of variables and the heterogeneity of the datasets to integrate. Recently, a lot of tools have been developed to solve the problem of integrating omics data including canonical correlation analysis, matrix factorization and SM. These commonly used techniques aim to analyze simultaneously two or more types of omics. In this article, we compare a panel of 13 unsupervised methods based on these different approaches to integrate various types of multi-omics datasets: iClusterPlus, regularized generalized canonical correlation analysis, sparse generalized canonical correlation analysis, multiple co-inertia analysis (MCIA), integrative-NMF (intNMF), SNF, MoCluster, mixKernel, CIMLR, LRAcluster, ConsensusClustering, PINSPlus and multi-omics factor analysis (MOFA). We evaluate the ability of the methods to recover the subgroups and the variables that drive the clustering on eight benchmarks of simulation. MOFA does not provide any results on these benchmarks. For clustering, SNF, MoCluster, CIMLR, LRAcluster, ConsensusClustering and intNMF provide the best results. For variable selection, MoCluster outperforms the others. However, the performance of the methods seems to depend on the heterogeneity of the datasets (especially for MCIA, intNMF and iClusterPlus). Finally, we apply the methods on three real studies with heterogeneous data and various phenotypes. We conclude that MoCluster is the best method to analyze these omics data. Availability: An R package named CrIMMix is available on GitHub at https://github.com/CNRGH/crimmix to reproduce all the results of this article.
Published: 2019

25. Bayesian Network Analysis of plasma microRNA sequencing data in patients with venous thrombosis

Author: Manal Ibrahim-Kosta, Jean-François Deleuze, Maguelonne Roux, Florian Thibord, Pierre-Emmanuel Morange, Pierre Suchon, Louisa Goumidi, David-Alexandre Trégouët, Claire Perret, Gaëlle Munsch, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé publique : épidémiologie & sciences de l'information biomédicale (ED 393), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset CEPH, F.T, G.M and M.G were financially supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013). DA.T was financially supported by the «EPIDEMIOM-VTE» Senior Chair from the Initiative of Excellence of the University of Bordeaux. MiRNA sequencing in the MARTHA study was performed on the iGenSeq platform (ICM Institute, Paris) and supported by a grant from the European Society of Cardiology for Medical Research Innovation. Bioinformatics and statistical analyses benefit from the CBiB computing centre of the University of Bordeaux., GENMED consortium, Tregouet, David, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre recherche en CardioVasculaire et Nutrition (C2VN), Centre National de Recherche en Génomique Humaine [Evry] (CNRGH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de Recherche en Génomique Humaine (CNRGH), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Admin, Oskar, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université de Paris (UP)
Subjects: Single-nucleotide polymorphism, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Bioinformatics, Genome Wide Association Study, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, plasma miRNA, Next generation sequencing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Venous thrombosis, medicine, Trombosis venosa, In patient, 030304 developmental biology, Genetic association, 0303 health sciences, Secuenciación de última generación, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genoma completo, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MicroRNA sequencing, business.industry, Articles, medicine.disease, Thrombosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Biomarcadores, VINTAGE, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Estudio de asociación, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: MicroRNAs (miRNAs) are small regulatory RNAs participating to several biological processes and known to be involved in various pathologies. Measurable in body fluids, miRNAs have been proposed to serve as efficient biomarkers for diseases and/or associated traits. Here, we performed a next-generation-sequencing based profiling of plasma miRNAs in 344 patients with venous thrombosis (VT) and assessed the association of plasma miRNA levels with several haemostatic traits and the risk of VT recurrence. Among the most significant findings, we detected an association between hsa-miR-199b-3p and haematocrit levels (P = 0.0016), these two markers having both been independently reported to associate with VT risk. We also observed suggestive evidence for association of hsa-miR-370-3p (P = 0.019), hsa-miR-27b-3p (P = 0.016) and hsa-miR-222-3p (P = 0.049) with VT recurrence, the observations at the latter two miRNAs confirming the recent findings of Wang et al. Besides, by conducting Genome-Wide Association Studies on miRNA levels and meta-analyzing our results with some publicly available, we identified 21 new associations of single nucleotide polymorphisms with plasma miRNA levels at the statistical significance threshold of P, Los micro-ARN (miARN) son pequeñas moléculas de ARN reguladoras que participan en varios procesos biológicos y están implicados en diversas patologías. Mensurables en los líquidos corporales, se ha planteado que los miARN pueden ser biomarcadores eficaces para el diagnóstico de enfermedades y/o características asociadas. Aquí hemos llevado a cabo un análisis de miARN plasmático con tecnología de secuenciación de última generación en 344 pacientes con trombosis venosa (TV) y hemos evaluado la asociación de los niveles de miARN con distintas características hemostáticas y el riesgo de recidiva de TV. Entre los hallazgos más significativos, hemos detectado una asociación entre hsa-miR-199b-3p y los niveles de hematocritos (p = 0,0016); dos marcadores que se habían asociado de forma independiente con el riesgo de sufrir TV. Asimismo, hemos observado una evidencia indicativa de asociación entre hsa-miR-370-3p (p = 0,019), hsa-miR-27b-3p (p = 0,016) y hsa-miR-222-3p (p = 0,049) y la recidiva de TV; los resultados los dos últimos miARN confirman los hallazgos recientes de Wang et al. (Clin Epigenetics, 2019). Además, al efectuar estudios de asociación del genoma completo sobre los niveles de miARN y al metaanalizar nuestros resultados con otros disponibles públicamente, hemos identificado 21 asociaciones nuevas de polimorfismos de un solo nucleótido (PSN) con niveles de miARN plasmático con un umbral de significación estadística de p
Published: 2019

26. Society, law, morality and bioethics: A systemic point of view

Author: Stoeklé, H.-C., Deleuze, J.-F., Vogt, G., CCSD, Accord Elsevier, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset CEPH, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Université de Paris (UP)
Subjects: [SHS] Humanities and Social Sciences, [SHS]Humanities and Social Sciences
Published: 2019

27. Low temperature isothermal amplification of microsatellites drastically reduces stutter artifact formation and improves microsatellite instability detection in cancer

Author: Antoine Daunay, Alex Duval, Olivier Buhard, Alexandre How-Kit, Laura G. Baudrin, Jean-François Deleuze, Victor Renault, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Fondation Jean Dausset CEPH, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Instabilité des microsatellites et cancers [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Instabilite des Microsatellites et Cancers, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Instabilité des microsatellites et cancers [CRSA], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: [SDV]Life Sciences [q-bio], Loop-mediated isothermal amplification, Recombinase Polymerase Amplification, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Genome, Frameshift mutation, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Cell Line, Tumor, Biomarkers, Tumor, Genetics, medicine, Humans, Polymerase, Polymerase chain reaction, 030304 developmental biology, 0303 health sciences, biology, Temperature, Microsatellite instability, DNA, medicine.disease, 030220 oncology & carcinogenesis, biology.protein, Methods Online, Microsatellite, Microsatellite Instability, Colorectal Neoplasms, Nucleic Acid Amplification Techniques, Microsatellite Repeats
Abstract: Microsatellites are polymorphic short tandem repeats of 1–6 nucleotides ubiquitously present in the genome that are extensively used in living organisms as genetic markers and in oncology to detect microsatellite instability (MSI). While the standard analysis method of microsatellites is based on PCR followed by capillary electrophoresis, it generates undesirable frameshift products known as ‘stutter peaks’ caused by the polymerase slippage that can greatly complicate the analysis and interpretation of the data. Here we present an easy multiplexable approach replacing PCR that is based on low temperature isothermal amplification using recombinase polymerase amplification (LT-RPA) that drastically reduces and sometimes completely abolishes the formation of stutter artifacts, thus greatly simplifying the calling of the alleles. Using HT17, a mononucleotide DNA repeat that was previously proposed as an optimal marker to detect MSI in tumor DNA, we showed that LT-RPA improves the limit of detection of MSI compared to PCR up to four times, notably for small deletions, and simplifies the identification of the mutant alleles. It was successfully applied to clinical colorectal cancer samples and enabled detection of MSI. This easy-to-handle, rapid and cost-effective approach may deeply improve the analysis of microsatellites in several biological and clinical applications.
Published: 2019

28. Untargeted mass spectrometry lipidomics identifies correlation between serum sphingomyelins and plasma cholesterol

Author: Alexandre Colleu, Essa Hariri, David Touboul, Pierre Zalloua, Jeremy K. Nicholson, Lyamine Hedjazi, Dominique Gauguier, Francois Brial, Hanane Kadar, Aurélie Le Lay, Mark Lathrop, Marc-Emmanuel Dumas, Justine Dubus, Layal Abi Farraj, Fumihiko Matsuda, Gestionnaire, Hal Sorbonne Université, Lebanese American University (LAU), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Graduate School of Medicine and Faculty of Medicine Kyoto University, McGill University and Genome Quebec Innovation Centre, Imperial College London, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Biomolecular Medicine, The Wellcome Trust Centre for Human Genetics [Oxford], and University of Oxford [Oxford]
Subjects: Male, Endocrinology, Diabetes and Metabolism, Metabolite, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Coronary Artery Disease, 030204 cardiovascular system & hematology, Mass Spectrometry, TOXICITY, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, HDL cholesterol, Medicine, ARTERY-DISEASE, lcsh:RC620-627, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.TOX.ECO] Life Sciences [q-bio]/Toxicology/Ecotoxicology, LARGE-SCALE, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Sphingomyelins, 3. Good health, Lipoproteins, LDL, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, lcsh:Nutritional diseases. Deficiency diseases, Cholesterol, Female, lipids (amino acids, peptides, and proteins), [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, Lipoproteins, HDL, Sphingomyelin, Life Sciences & Biomedicine, [CHIM.CHEM]Chemical Sciences/Cheminformatics, Lipidology, Adult, medicine.medical_specialty, Biochemistry & Molecular Biology, [CHIM.ANAL] Chemical Sciences/Analytical chemistry, Adolescent, Clinical chemistry, Lipoproteins, 030209 endocrinology & metabolism, Clinical nutrition, METABOLISM, 0899 Other Information And Computing Sciences, UPLC-MS, Gas Chromatography-Mass Spectrometry, Young Adult, 03 medical and health sciences, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, RISK-FACTOR, Internal medicine, Lipidomics, 1101 Medical Biochemistry And Metabolomics, Humans, Metabolomics, [CHIM]Chemical Sciences, CORONARY-HEART-DISEASE, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Aged, Sphingolipids, Science & Technology, Nutrition & Dietetics, business.industry, Research, Biochemistry (medical), medicine.disease, Sphingolipid, [SDE.BE] Environmental Sciences/Biodiversity and Ecology, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, chemistry, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, business, [CHIM.OTHE]Chemical Sciences/Other
Abstract: Background Lipoproteins are major players in the development and progression of atherosclerotic plaques leading to coronary stenosis and myocardial infarction. Epidemiological, genetic and experimental observations have implicated the association of sphingolipids and intermediates of sphingolipid synthesis in atherosclerosis. We aimed to investigate relationships between quantitative changes in serum sphingolipids, the regulation of the metabolism of lipoproteins (LDL, HDL), and endophenotypes of coronary artery disease (CAD). Methods We carried out untargeted liquid chromatography – mass spectrometry (UPLC-MS) lipidomics of serum samples of subjects belonging to a cross-sectional study and recruited on the basis of absence or presence of angiographically-defined CAD, and extensively characterized for clinical and biochemical phenotypes. Results Among the 2998 spectral features detected in the serum samples, 1328 metabolic features were significantly correlated with at least one of the clinical or biochemical phenotypes measured in the cohort. We found evidence of significant associations between 34 metabolite signals, corresponding to a set of sphingomyelins, and serum HDL cholesterol. Many of these metabolite associations were also observed with serum LDL and total cholesterol levels but not as much with serum triglycerides. Conclusion Among patients with CAD, sphingolipids in the form of sphingomyelins are directly correlated with serum levels of lipoproteins and total cholesterol. Results from this study support the fundamental role of sphingolipids in modulating lipid serum levels, highlighting the importance to identify novel targets in the sphingolipid metabolic pathway for anti-atherogenic therapies. Electronic supplementary material The online version of this article (10.1186/s12944-018-0948-5) contains supplementary material, which is available to authorized users.
Published: 2018

29. Improved Microsatellite Instability Detection and Identification by Nuclease-Assisted Microsatellite Instability Enrichment Using HSP110 T17

Author: Hung Bui, Alex Duval, Antoine Daunay, Laura G. Baudrin, Alexandre How-Kit, Olivier Buhard, Jean-François Deleuze, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Genetic predisposition, medicine, Biomarkers, Tumor, Humans, neoplasms, ComputingMilieux_MISCELLANEOUS, Mutation, Biochemistry (medical), Microsatellite instability, medicine.disease, digestive system diseases, Immune checkpoint, Lynch syndrome, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Biomarker (medicine), Microsatellite, DNA mismatch repair, Female, Microsatellite Instability, Colorectal Neoplasms
Abstract: To the Editor: Microsatellite instability (MSI)1 is characterized by the accumulation of mutations (insertions or deletions of several nucleotides) in microsatellites, caused by DNA mismatch repair system deficiency. Approximately 15% to 20% of colorectal cancers (CRCs) present with MSI, the origin of which can be sporadic or owing to genetic predisposition to Lynch syndrome/hereditary nonpolyposis CRC or constitutional mismatch repair deficiency syndrome. The MSI phenotype is associated with a better survival rate for patients with stage II/III CRC and is also a major predictive biomarker for the efficacy of immune checkpoint blockade therapy in metastatic CRC. The gold standard method for MSI detection includes standard PCR followed by fragment analysis using the Bethesda or the Pentaplex panel, each composed of 5 microsatellite markers. However, this approach can lack analytical sensitivity, thus limiting potential clinical applications. Recent attempts to improve the analytical sensitivity of MSI detection include a method based on mutation enrichment during E- ice -COLD-PCR. This method uses HSP110 T17 (HT17), which, compared with the Pentaplex panel, is an improved microsatellite biomarker for the diagnosis of MSI/MSI-High in CRC and also bears prognostic and predictive information …
Published: 2018

30. Major improvement in the detection of microsatellite instability in colorectal cancer using HSP110 T17 E-ice-COLD-PCR

Author: Mourad Sahbatou, Jean-François Deleuze, Alexandre How-Kit, Ada Collura, Antoine Daunay, Olivier Buhard, Alex Duval, Clément Meiller, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Colorectal cancer, MSI detection method, [SDV]Life Sciences [q-bio], E-ice-COLD-PCR, colorectal cancer, Biology, Polymerase Chain Reaction, Germline, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Genotype, Genetics, medicine, Humans, HSP110 Heat-Shock Proteins, Allele, neoplasms, Genetics (clinical), COLD-PCR, Microsatellite instability, Reference Standards, medicine.disease, Molecular biology, Lynch syndrome, digestive system diseases, 3. Good health, Cold Temperature, Germ Cells, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Mutation, microsatellite instability, Colorectal Neoplasms, DNA, HSP110
Abstract: International audience; Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI) to screen for Lynch syndrome. Evaluation of MSI status involves screening tumor DNA for the presence of somatic deletions in DNA repeats using PCR followed by fragment analysis. While this method may lack sensitivity due to the presence of a high level of germline DNA, which frequently contaminates the core of primary colon tumors, no other method developed to date is capable of modifying the standard PCR protocol to achieve improvement of MSI detection. Here, we describe a new approach developed for the ultra-sensitive detection of MSI in CRC based on E-ice-COLDPCR, using HSP110 T17, a mononucleotide DNA repeat previously proposed as an optimal marker to detect MSI in tumor DNA, and an oligo(dT)(16) LNA blocker probe complementary to wild-type genotypes. The HT17 E-ice-COLD-PCR assay improved MSI detection by 20-200-fold compared with standard PCR using HT17 alone. It presents an analytical sensitivity of 0.1%-0.05% of mutant alleles in wild-type background, thus greatly improving MSI detection in CRC samples highly contaminated with normal DNA. HT17 E-ice-COLD-PCR is a rapid, cost-effective, easy-to-implement, and highly sensitive method, which could significantly improve the detection of MSI in routine clinical testing.
Published: 2018

31. Immunochip analysis identifies association of the RAD50/IL13 region with human longevity

Author: Martina Müller-Nurasyid, Amke Caliebe, Céline Derbois, Friederike Flachsbart, Carsten Büning, Anette Peters, Pilar Galan, Per Hoffmann, Marianne Nygaard, Stephan Brand, Stefan Schreiber, Femke-Anouska Heinsen, Almut Nebel, Andre Franke, Markus M. Nöthen, Wolfgang Lieb, Liljana Gentschew, Kaare Christensen, David Ellinghaus, Lene Christiansen, Hélène Blanché, Konstantin Strauch, Jean-François Deleuze, Institute of Clinical Molecular Biology, Kiel University, Christian-Albrechts University of Kiel, University of Southern Denmark (SDU), Department of Clinical Genetics, Odense University Hospital, Odense University Hospital (OUH), Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Université Sorbonne Paris Cité (COMUE) (USPC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Ludwig Maximilians University of Munich, Institute of Epidemiology, Helmholtz-Zentrum München (HZM), Munich Heart Alliance, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Institute of Human Genetics, Universität Ulm - Ulm University [Ulm, Allemagne], Department of Genomics, Life and Brain Center, University of Bonn, Department of Biomedicine, University of Bergen (UiB), University Hospital Basel [Basel], University Medical Center Schleswig-Holstein, RESOLVE project [FP7-HEALTH-F4-2008-202047], Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence 'Inflammation at Interfaces', German Federal Ministry of Education and Research (BMBF) [01ZX1306A], German Ministry for Education and Research [01EY1103], German Federal Ministry for Education and Research within the context of the National Genome Research Network 2 [NGFN-2], National Genome Research Network plus (NGFNplus), Integrated Genome Research Network (IG) MooDS [01GS08144, 01GS08147], INTER-REG4A program Syddanmark-Schleswig-K.E.R.N, EU funds from the European Regional Development Fund, VELUX Foundation, Danish National Research Foundation, US National Institutes of Health-National Institute on Aging [P01 AG08761], Danish Agency for Science, Technology and Innovation [09-070081], French Institut National de la Sante et de la Recherche Medicale, Institut National de la Recherche Agronomique, the Universite Paris 13, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, German Federal Ministry of Education and Research, State of Bavaria, Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-University Munich, as part of LMUinnovativ, DFG [BR1912/6-1], Else-Kroner-Fresenius-Stiftung [2010_EKES.32], Alfried Krupp von Bohlen und Halbach-Stiftung, Heinz Nixdorf Foundation (Germany), German Ministry of Education and Science, German Research Council (DFG) [SI 236/8-1, SI236/9-1, ER 155/61], Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig-Maximilians University [Munich] (LMU), Helmholtz Zentrum München = German Research Center for Environmental Health, Universität Bonn = University of Bonn, ProdInra, Migration, Flachsbart, Friederike, and Ellinghaus, David
Subjects: 0301 basic medicine, Il13, Rad50, 5q31.1, Immunochip, Genetic Association, Human Longevity, Aging, IL 13, genetic association, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Longevity, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, 030105 genetics & heredity, Biology, Danish, 03 medical and health sciences, Humans, SNP, chromosome, 5q31, human longevity, IL13, RAD50, longévité, Oligonucleotide Array Sequence Analysis, media_common, Genetic association, Short Takes, Genetics, Interleukin-13, Short Take, Cell Biology, language.human_language, Acid Anhydride Hydrolases, 3. Good health, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], DNA Repair Enzymes, 030104 developmental biology, Genetic Loci, Multiple comparisons problem, language, Chromosomes, Human, Pair 5, Genome-Wide Association Study
Abstract: Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long-lived individuals (LLI) and 8919 younger controls. First, we performed a large-scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune-associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip-wide significant signal (PI mmunochip = 7.01 × 10-9 ) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip < 5 × 10-4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta-analysis of the combined French and Danish data after adjusting for multiple testing. In a meta-analysis of all three samples, rs2706372 reached a P-value of PI mmunochip+Repl = 5.42 × 10-7 (OR = 1.20; 95% CI = 1.12-1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life. Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long-lived individuals (LLI) and 8919 younger controls. First, we performed a large-scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune-associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip-wide significant signal (PI mmunochip = 7.01 × 10(-9) ) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip < 5 × 10(-4) for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta-analysis of the combined French and Danish data after adjusting for multiple testing. In a meta-analysis of all three samples, rs2706372 reached a P-value of PI mmunochip+Repl = 5.42 × 10(-7) (OR = 1.20; 95% CI = 1.12-1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.
Published: 2016

32. Network Modeling of Crohn's Disease Incidence

Author: Gilles Wainrib, Jean-Pierre Hugot, Gaëlle Debret, Annick Lesne, Pascal Carrivain, Jean-Marc Victor, Leigh Pascoe, Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL), Université Sorbonne Paris Cité (USPC), Origine, structure et évolution de la biodiversité (OSEB), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), and École normale supérieure - Paris (ENS Paris)
Subjects: 0301 basic medicine, Male, lcsh:Medicine, Genome-wide association study, Disease, Genetic Networks, Crohn Disease, Risk Factors, Odds Ratio, Medicine and Health Sciences, Gene Regulatory Networks, lcsh:Science, Crohn's disease, Multidisciplinary, Incidence, Genomics, Colitis, Ulcerative colitis, Markov Chains, 3. Good health, Female, Network Analysis, Research Article, Adult, Computer and Information Sciences, Multiple Sclerosis, Gastroenterology and Hepatology, 03 medical and health sciences, Genetic Disorders, medicine, Genetics, Genome-Wide Association Studies, Humans, Ulcerative Colitis, Computer Simulation, Spondylitis, Ankylosing, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Alleles, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Ankylosing spondylitis, Models, Genetic, business.industry, Multiple sclerosis, lcsh:R, Inflammatory Bowel Disease, Biology and Life Sciences, Computational Biology, Epistasis, Genetic, Human Genetics, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Odds ratio, medicine.disease, Genome Analysis, 030104 developmental biology, Genetic Loci, Immunology, Genetics of Disease, Schizophrenia, lcsh:Q, Colitis, Ulcerative, Gene-Environment Interaction, Personalized medicine, business
Abstract: International audience; BACKGROUND: Numerous genetic and environmental risk factors play a role in human complex genetic disorders (CGD). However, their complex interplay remains to be modelled and explained in terms of disease mechanisms.METHODS AND FINDINGS: Crohn's Disease (CD) was modeled as a modular network of patho-physiological functions, each summarizing multiple gene-gene and gene-environment interactions. The disease resulted from one or few specific combinations of module functional states. Network aging dynamics was able to reproduce age-specific CD incidence curves as well as their variations over the past century in Western countries. Within the model, we translated the odds ratios (OR) associated to at-risk alleles in terms of disease propensities of the functional modules. Finally, the model was successfully applied to other CGD including ulcerative colitis, ankylosing spondylitis, multiple sclerosis and schizophrenia.CONCLUSION: Modeling disease incidence may help to understand disease causative chains, to delineate the potential of personalized medicine, and to monitor epidemiological changes in CGD.
Published: 2016

33. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Author: Debette, Stéphanie, Kamatani, Yoichiro, Wolf, Christiane, Agabiti Rosei, Enrico, Lanfranconi, Silvia, Ferrarese, Carlo, Susani, Emanuela, Bicocca, Milano, Giacalone, Giacomo, Paolucci, Stefano, Palmirotta, Raffaele, Paciaroni, Maurizio, Ballabio, Elena, Dittrich, Ralf, Parati, Eugenio A, Ciusani, Emilio, Fluri, Felix, Hatz, Florian, Gisler, Dominique, Amort, Margareth, Bevan, Steve, James, Tom, Olsson, Sandra, Holmegaard, Lukas, Touzé, Emmanuel, Altintas, Ayse, Martin, Juan José, Kittner, Steven, MItchell, Braxton, Stine, Colin, O'Connell, Jeff, Dueker, Nicole, Koudstaal, Peter J, de Lau, Lonneke M L, Hofman, Albert, Southerland, Andrew M, Verhaaren, Benjamin F, Uitterlinden, Andre G, Montaner, Joan, Mendioroz, Maite, Yadav, Sunaina, Khan, Muhammad Saleem, Wilder, Michael, van Dijk, Ewoud, Maaijwee, Noortje, Rutten-Jacobs, Loes, Samson, Yves, Kramer, Jamie, Malik, Shaneela, Brott, Thomas G, Brown, Robert D, Singleton, Andrew, Hardy, John, Rich, Stephen S, Tanislav, Christian, Jungehülsing, Jan, Abboud, Shérine, Béjot, Yannick, Caso, Valeria, Bersano, Anna, Gschwendtner, Andreas, Metso, Tiina M, Sessa, Maria, Cole, John, Lamy, Chantal, Medeiros, Elisabeth, Beretta, Simone, Bonati, Leo H, Grau, Armin J, Michel, Patrik, Majersik, Jennifer J, Sharma, Pankaj, Kloss, Manja, Kalashnikova, Ludmila, Nazarova, Maria, Dobrynina, Larisa, Bartels, Eva, Guillon, Benoit, van den Herik, Evita G, Fernandez-Cadenas, Israel, Jood, Katarina, Nalls, Michael A, De Leeuw, Frank-Erik, Chauhan, Ganesh, Jern, Christina, Cheng, Yu-Ching, Werner, Inge, Metso, Antti J, Lichy, Christoph, Lyrer, Philippe A, Brandt, Tobias, Boncoraglio, Giorgio B, Wichmann, Heinz-Erich, Gieger, Christian, Engelter, Stefan T, Johnson, Andrew D, Böttcher, Thomas, Castellano, Maurizio, Arveiler, Dominique, Ikram, M Arfan, Breteler, Monique M B, Padovani, Alessandro, Meschia, James F, Kuhlenbäumer, Gregor, Rolfs, Arndt, Pezzini, Alessandro, Worrall, Bradford B, Consortium, International Stroke Genetics, Ringelstein, Erich-Bernd, Zelenika, Diana, Tatlisumak, Turgut, Lathrop, Mark, Leys, Didier, Amouyel, Philippe, Dallongeville, Jean, Group, CADISP, Thijs, Vincent, Lemmens, Robin, Pandolfo, Massimo, Bodenant, Marie, Louillet, Fabien, Mas, Jean-Louis, Deltour, Sandrine, Leder, Sara, Léger, Anne, Canaple, Sandrine, Godefroy, Olivier, Markus, Hugh S, Giroud, Maurice, Jacquin, Agnès, Moulin, Thierry, Vullier, Fabrice, Tzourio, Christophe, Dos Santos, Michael, Malik, Rainer, Hausser, Ingrid, Thomas-Feles, Constanze, Weber, Ralf, Dichgans, Martin, Grond-Ginsbach, Caspar, Hacke, Werner, Giossi, Alessia, Volonghi, Irene, Costa, Paolo, del Zotto, Elisabetta, Morotti, Andrea, Poli, Loris, Lorenza Muiesan, Maria, Salvetti, Massimo, Epidémiologie des maladies chroniques: impact des intéractions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Epidemiologie-Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Helsinki University Central Hospital [Finland] (HUCH), Heidelberg University Hospital [Heidelberg], University Hospital Basel [Basel], Università degli Studi di Brescia = University of Brescia (UniBs), University Hospitals Leuven [Leuven], Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), University of Cambridge [UK] (CAM), Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), Ludwig-Maximilians-Universität München (LMU), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), University of Virginia, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neurochirurgie Expérimentale [Brussels] (ULB 257), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Perugia = University of Perugia (UNIPG), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Ospedale San Raffaele, University of Maryland School of Medicine, University of Maryland System, Service de neurologie [Amiens], CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Klinikum Ludwigshafen [Germany], Service of Neurology [CHUV, Lausanne, Switzerland], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Utah School of Medicine [Salt Lake City], Institute of Cardiovascular Research (ICR2UL), Royal Holloway [University of London] (RHUL), Ashford and St Peter's hospitals NHS foundation trust, Russian Academy of Sciences [Moscow] (RAS), Centre for Cognition and Decision Making [HSE, Moscow], Institut of Cognitive Neuroscience [HSE, Moscow] (ICN), Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE)-Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE), Zentrum für neurologische Gefäßdiagnostik - Center for Neurological Vascular Diagnostics [Munich, Germany], Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Department of Neurology [Erasmus MC, Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital Universitario Mutua de Terrassa, Vall d'Hebron University Hospital [Barcelona], Insitute of Neuroscience and Physiology, University of Gothenburg (GU), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Schmieder Klinik [Heidelberg, Germany], Helmholtz Zentrum München = German Research Center for Environmental Health, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University Hospital Rostock, Progression tumorale et microenvironnement. Approches translationnelles et épidémiologie, Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Institut Régional du Cancer-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Brescia, Mayo Clinic [Jacksonville], Institute of Experimental Medicine - Institut für Experimentelle Medizin [Kiel, Germany] (IEM), Christian-Albrechts-Universität zu Kiel (CAU), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, McGill University and Genome Quebec Innovation Centre, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Pharmacologie de la mort neuronale et de la plasticité cérébrale, IFR114-Université de Lille, Droit et Santé, Réseau International des Instituts Pasteur (RIIP), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, The CADISP study has been supported by INSERM, Lille 2 University, Institut Pasteur de Lille and Lille University Hospital and received funding from the European Regional Development Fund (FEDER funds) and Région Nord-Pas-de-Calais in the framework of Contrat de Projets Etat-Region 2007–2013 Région Nord-Pas-de-Calais (grant 09120030), Centre National de Génotypage, the Emil Aaltonen Foundation, the Paavo Ilmari Ahvenainen Foundation, the Helsinki University Central Hospital Research Fund, the Helsinki University Medical Foundation, the Päivikki and Sakari Sohlberg Foundation, the Aarne Koskelo Foundation, the Maire Taponen Foundation, the Aarne and Aili Turunen Foundation, the Lilly Foundation, the Alfred Kordelin Foundation, the Finnish Medical Foundation, the Orion Farmos Research Foundation, the Maud Kuistila Foundation, the Finnish Brain Foundation, the Biomedicum Helsinki Foundation, Projet Hospitalier de Recherche Clinique Régional, Fondation de France, Génopôle de Lille, Adrinord, the Basel Stroke Funds, the Käthe-Zingg-Schwichtenberg-Fonds of the Swiss Academy of Medical Sciences and the Swiss Heart Foundation.L.H.B., S.T.E. and P.A.L. were supported, in part, by a grant from the Swiss National Science Foundation (33CM30-124119). S.D. is supported by a Chair of Excellence from the French National Research Agency (ANR). S.D. and M.D. are supported by a grant from the Leducq Foundation. M.D. is supported by the Vascular Dementia Research Foundation. I.F.-C. is supported by the Miguel Servet programme (CP12/03298) from the Spanish Ministry of Health (Instituto de Salud Carlos III). G.K. is a member of the Deutsche Forschungsgemeinschaft Cluster of Excellence 'Inflammation at Interfaces'. P.S. is supported by a Department of Health (UK) senior fellowship. A.M.S. is supported by the American Heart Association/American Stroke Association National Clinical Research Program (AHA 3CRP14140001). V.T. is supported by Fonds Wetenschappelijk Onderzoek Flanders., CADISP Group, RIKEN Center for Integrative Medical Science, Università degli Studi di Brescia [Brescia], University of Virginia [Charlottesville], Service des Urgences Cérébro-Vasculaires [CHU Pitié-Salpêtrière]], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Laboratoire de Neurologie Expérimentale [ULB, Brussels, Belgium] (ULB 257), Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Università degli Studi di Perugia (UNIPG), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), National Research University Higher School of Economics [Moscow] (HSE)-National Research University Higher School of Economics [Moscow] (HSE), Radboud university [Nijmegen], Helmholtz-Zentrum München (HZM), Westfälische Wilhelms-Universität Münster (WWU), The authors thank the staff and participants of all CADISP centers for their important contributions., Service des Urgences Cérébro-Vasculaires [CHU Pitié-Salpétriêre], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Erasmus MC other, Epidemiology, Debette, S, Kamatani, Y, Metso, T, Kloss, M, Chauhan, G, Engelter, S, Pezzini, A, Thijs, V, Markus, H, Dichgans, M, Wolf, C, Dittrich, R, Touzé, E, Southerland, A, Samson, Y, Abboud, S, Béjot, Y, Caso, V, Bersano, A, Gschwendtner, A, Sessa, M, Cole, J, Lamy, C, Medeiros, E, Beretta, S, Bonati, L, Grau, A, Michel, P, Majersik, J, Sharma, P, Kalashnikova, L, Nazarova, M, Dobrynina, L, Bartels, E, Guillon, B, Van Den Herik, E, Fernandez Cadenas, I, Jood, K, Nalls, M, De Leeuw, F, Jern, C, Cheng, Y, Werner, I, Metso, A, Lichy, C, Lyrer, P, Brandt, T, Boncoraglio, G, Wichmann, H, Gieger, C, Johnson, A, Böttcher, T, Castellano, M, Arveiler, D, Ikram, M, Breteler, M, Padovani, A, Meschia, J, Kuhlenbäumer, G, Rolfs, A, Worrall, B, Ringelstein, E, Zelenika, D, Tatlisumak, T, Lathrop, M, Leys, D, Amouyel, P, Dallongeville, J, Lemmens R, P, and Ferrarese, C
Subjects: Male, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Myocardial Infarction, Genome-wide association study, Carotid Artery, Internal, Dissection, Gastroenterology, epidemiology [Carotid Artery, Internal, Dissection], Brain Ischemia, 0302 clinical medicine, Migraine Disorder, Odds Ratio, Finland, Vertebral Artery Dissection, 0303 health sciences, education.field_of_study, epidemiology [Hypercholesterolemia], MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Phactr-1 protein, human, MESH: Brain Ischemia, MESH: Follow-Up Studies, 3. Good health, MESH: Myocardial Infarction, Human, medicine.medical_specialty, Migraine Disorders, Hypercholesterolemia, MESH: Vertebral Artery Dissection, Lower risk, genetics [Brain Ischemia], Article, Follow-Up Studie, MESH: Carotid Artery, Internal, Dissection, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, genetics [Carotid Artery, Internal, Dissection], Genetics, Genetic predisposition, epidemiology [Brain Ischemia], Humans, epidemiology [Vertebral Artery Dissection], Polymorphism, education, Alleles, MESH: Humans, genetics [Vertebral Artery Dissection], MESH: Adult, Odds ratio, Microfilament Protein, medicine.disease, Adult, Female, Follow-Up Studies, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Hypertension, Microfilament Proteins, Middle Aged, Obesity, Risk Factors, Polymorphism, Single Nucleotide, MESH: Genome-Wide Association Study, Carotid Artery, MESH: Female, 030217 neurology & neurosurgery, epidemiology [Finland], Cervical Artery, Vertebral artery dissection, epidemiology [Hypertension], MESH: Hypertension, MESH: Risk Factors, MESH: Obesity, Stroke, Allele, Dissection, MESH: Finland, MESH: Genetic Predisposition to Disease, MESH: Hypercholesterolemia, Single Nucleotide, MESH: Migraine Disorders, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], epidemiology [Myocardial Infarction], [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Population, MESH: Genetic Pleiotropy, physiology [Microfilament Proteins], Biology, MESH: Microfilament Proteins, Internal medicine, ddc:570, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, 030304 developmental biology, epidemiology [Obesity], Risk Factor, MESH: Alleles, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Internal, MESH: Odds Ratio, MESH: Male, epidemiology [Migraine Disorders], genetics [Microfilament Proteins]
Abstract: Item does not contain fulltext Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 x 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 x 10(-3); combined P = 1.00 x 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
Published: 2015

34. A DEMETER-like DNA demethylase governs tomato fruit ripening

Author: Chaoqun Wu, Mickaël Maucourt, Mingchun Liu, Mondher Bouzayen, Graham B. Seymour, Anne Mortain-Bertrand, Dominique Rolin, Ruie Liu, Junhua Kong, Emeline Teyssier, Jörg Tost, Yiguo Hong, T. Charlie Hodgman, Charlotte Degraeve-Guibault, Linda Stammitti, Natalie H. Chapman, Philippe Gallusci, Stefanie Halle, James J. Giovannoni, Alexandre How-Kit, Biologie du fruit et pathologie (BFP), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1, Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain, Génomique et Biotechnologie des Fruits (GBF), Institut National de la Recherche Agronomique (INRA)-École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Hangzhou Normal University, University of Nottingham, UK (UON), Boyce Thompson Institute [Ithaca], Commissariat à l'Energie Atomique et aux énergies alternatives - CEA (FRANCE), Cornell University (USA), Institut National Polytechnique de Toulouse - INPT (FRANCE), Institut National de la Recherche Agronomique - INRA (FRANCE), University of Nottingham (UNITED KINGDOM), University of Warwick (UNITED KINGDOM), Fondation Jean Dausset - Centre d’Etude du Polymorphisme Humain - CEPH (FRANCE), Hangzhou Normal University - HZNU (CHINA), Université de Bordeaux (FRANCE), Laboratoire Epigénétique et Environnement - LEE (Evry,France), and Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)
Subjects: DNA, Plant, fruit ripening, Biology, tomato, Genes, Plant, Tomato, DNA Glycosylases, DNA glycosylase lyase, active DNA demethylation, epigenetic, physiologie végétale, chemistry.chemical_compound, Solanum lycopersicum, Gene Expression Regulation, Plant, Génétique des plantes, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Epigenetics, Gene, Plant Proteins, Demethylation, 2. Zero hunger, Genetics, Vegetal Biology, Multidisciplinary, fungi, Epigenetic, food and beverages, Ripening, DNA Methylation, Biological Sciences, Fruit ripening, Plants, Genetically Modified, Cell biology, DNA demethylation, chemistry, Fruit, développement du fruit, DNA methylation, biology.protein, Demethylase, RNA Interference, Active DNA demethylation, Biologie végétale, Sciences agricoles, DNA
Abstract: International audience; In plants, genomic DNA methylation which contributes to development and stress responses can be actively removed by DEMETER-like DNA demethylases (DMLs). Indeed, in Arabidopsis DMLs are important for maternal imprinting and endosperm demethylation, but only a few studies demonstrate the developmental roles of active DNA demethylation conclusively in this plant. Here, we show a direct cause and effect relationship between active DNA demethylation mainly mediated by the tomato DML, SlDML2, and fruit ripening- an important developmental process unique to plants. RNAi SlDML2 knockdown results in ripening inhibition via hypermethylation and repression of the expression of genes encoding ripening transcription factors and rate-limiting enzymes of key biochemical processes such as carotenoid synthesis. Our data demonstrate that active DNA demethylation is central to the control of ripening in tomato.
Published: 2015

35. Epidemiologic study of the genetics and environment of asthma, bronchial hyperresponsiveness, and atopy

Author: Francine Kauffmann, Régis Matran, Valérie Siroux, Isabella Annesi-Maesano, Marie-Pierre Oryszczyn, Frédéric Gormand, Florence Demenais, Marie-Hélène Dizier, Alain Grimfeld, J Hochez, Denis Charpin, Françoise Neukirch, Jean Bousquet, Nicole Le Moual, Josué Feingold, Mark Lathrop, Isabelle Pin, Evelyne Paty, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service Pneumologie – Allergologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital nord, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Unité Asthme et allergologie, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie Allergologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de pédiatrie, CHU Grenoble-Hôpital Michallon, Kauffmann F, MH Dizier, A Grimfeld, Hochez J, M Lathrop, R Matran, Neukirch F, Paty E, Pin I, F Demenais ., Oryszczyn MP, Le Moual N, Siroux V, Annesi-Maesano I, Bousquet J, Charpin D, Feingold J, Gormand F, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Assistance Publique - Hôpitaux de Marseille (APHM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Epidémiologie des maladies infectieuses et modélisation ( ESIM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hôpital nord, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), CHU Trousseau [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Unité Asthme et allergologie [CHU Trousseau], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Pulmonary and Respiratory Medicine, Hypersensitivity, Immediate, Candidate gene, Allergy, MESH: Asthma, Job-exposure matrix, MESH: Environmental Exposure, 030232 urology & nephrology, MESH : Bronchial Hyperreactivity, Critical Care and Intensive Care Medicine, MESH : Asthma, MESH : Hypersensitivity, Immediate, Genetic determinism, Atopy, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Asthma, Genetics, 0303 health sciences, MESH: Humans, business.industry, MESH : Humans, Case-control study, MESH: Bronchial Hyperreactivity, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Environmental Exposure, medicine.disease, MESH : Risk Factors, respiratory tract diseases, 3. Good health, Bronchial hyperresponsiveness, Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Bronchial Hyperreactivity, MESH: Hypersensitivity, Immediate, Cardiology and Cardiovascular Medicine, business, MESH : Environmental Exposure
Abstract: T he Epidemiologic Study on the Genetics and Environment of Asthma (EGEA) was planned to assess genetic and environmental risk factors and their interactions in patients with asthma and for the two related traits of bronchial hyperresponsiveness and atopy. The study was performed from 1991 to 1995 and combined a case control study and a study of the families of the asthmatic patients. A synthesis of the results already obtained is presented. Smoking was related to IgE levels, even in asthma patients. Smoking was clearly related to the clinical severity of the asthma, which is clinically insufficiently taken into account. The relationships of occupational exposures to asthma have been assessed using a job exposure matrix. Segregation analyses of IgE have shown, after correction for the mode of ascertainment, the existence of a dominant major gene and a familial residual correlation. A systematic genome screen used in families with two asthmatic siblings showed a linkage of various regions in the genome that are related to asthma or related phenotypes (ie, 1p, 11p, 11q, 12q, 13q, 17q, and 19q), results that are in agreement with those of genome screens used in other studies. Regarding candidate genes, no association was shown between asthma and the F508 mutation of the cystic fibrosis gene. The analysis is still in progress with studies on the heterogeneity of asthma, with refined genetic studies, and by searching to integrate the results regarding environmental and genetic factors and studying their interactions.

36. FSuite: exploiting inbreeding in dense SNP chip and exome data

Author: Mourad Sahbatou, Anne-Louise Leutenegger, Marie-Claude Babron, Emmanuelle Génin, Steven Gazal, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université Paris-Sud - Paris 11 (UP11), Fondation Jean Dausset CEPH, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and Gazal, Steven
Subjects: Statistics and Probability, Population, Genomics, Consanguinity, Computational biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Biochemistry, Polymorphism, Single Nucleotide, Humans, Exome, education, Molecular Biology, Genetics, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, Homozygote, Disease gene identification, Computer Science Applications, SNP genotyping, Computational Mathematics, Identification (information), Computational Theory and Mathematics, Inbreeding, Software
Abstract: Summary: FSuite is a user-friendly pipeline developed for exploiting inbreeding information derived from human genomic data. It can make use of single nucleotide polymorphism chip or exome data. Compared with other software, the advantage of FSuite is that it provides a complete suite of scripts to describe and use the inbreeding information. It includes a module to detect inbred individuals and estimate their inbreeding coefficient, a module to describe the proportion of different mating types in the population and the individual probability to be offspring of different mating types that can be useful for population genetic studies. It also allows the identification of shared regions of homozygosity between affected individuals (homozygosity mapping) that can be used to identify rare recessive mutations involved in monogenic or multifactorial diseases. Availability and implementation: FSuite is developed in Perl and uses R functions to generate graphical outputs. This pipeline is freely available under GNU GPL license at: http://genestat.cephb.fr/software/index.php/FSuite . Contact: fsuite.software@gmail.com or steven.gazal@inserm.fr Supplementary information: Supplementary data is available at Bioinformatics online.
Published: 2014

37. Identification of Regions of the Escherichia coli Chromosome Specific for Neonatal Meningitis-Associated Strains

Author: J. C. Beaudoin, Xavier Nassif, Olivier Clermont, Stéphane Bonacorsi, Colin Tinsley, Edouard Bingen, I. le Gall, Jacques Elion, Université Paris Diderot - Paris 7 (UPD7), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Pharmacogénétique et abords thérapeutiques des maladies héréditaires, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Tinsley, Colin
Subjects: Immunology, Fimbria, Virulence, Molecular Genomics, Locus (genetics), Biology, medicine.disease_cause, Microbiology, Species Specificity, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Escherichia coli, medicine, Meningitis, Genomic library, Gene, Gene Library, Genetics, Models, Genetic, Chromosome Mapping, Nucleic Acid Hybridization, Chromosomes, Bacterial, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Pathogenicity island, Blotting, Southern, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Parasitology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Representational difference analysis
Abstract: Specific virulence factors associated with the pathogenesis of Escherichia coli strains causing neonatal meningitis (ECNM), such as the K1 capsular polysaccharide, the S fimbriae, and the Ibe10 protein, have been previously identified. However, some other yet unidentified factors are likely to be involved in the pathogenesis of ECNM. To identify specialized unique DNA regions associated with ECNM virulence, we used the representational difference analysis technique. The genomes of two strains belonging to nonpathogenic phylogenetic group A of the ECOR reference collection were subtracted from E. coli strain C5, isolated from a case of neonatal meningitis. Strain C5 belongs to the phylogenetic group B2 as do the majority of ECNM. We have isolated and mapped 64 DNA fragments which are specific for strain C5 and not found in nonpathogenic strains. Of these clones, 44 were clustered in six distinct regions on the chromosome. The sfa and ibe10 genes were located in regions 2 and 6, respectively. A group of genes ( cnf1 , hra , hly , and prs ) known to be present in a pathogenicity island of the uropathogenic strain E. coli J96 colocalized with region 6. The occurrence of these DNA regions was tested in a set of meningitis-associated strains and in a control group composed of non-meningitis-associated strains belonging to the same B2 group. Regions 1, 3, and 4 were present in 91, 82, and 81%, respectively, of the meningitis strains and in 40, 13, and 47% of the control strains. Together, these data suggest that regions 1, 3, and 4 code for factors associated with the ability of E. coli to invade the meninges of neonates.
Published: 2000

38. A variant in FTO shows association with melanoma risk not due to BMI

Author: Kristin Thorisdottir, Giovanna Bianchi Scarrà, Julia A. Newton Bishop, Elizabeth M. Gillanders, Jeffrey E. Lee, Katja K.H. Aben, Patricia Van Belle, Mark M. Iles, Ichiro Okamoto, John C. Taylor, Håkan Olsson, Veronica Höiom, Marjolein Janssen, Ketty Peris, Susana Puig, Lambertus A. Kiemeney, Anders Molven, Srdjan Novaković, Joan Anton Puig-Butille, Marko Hočevar, G. Mark Lathrop, Fengju Song, Lars A. Akslen, Bert Bakker, Jón Ólafsson, D. Timothy Bishop, Wilma Bergman, Nienke van der Stoep, Bardur Sigurgeirsson, Mark Harland, John L. Hopper, Stuart MacGregor, Graham J. Mann, Donato Calista, Celia Requena, Diana Zelenika, Mingfeng Zhang, Pilar Galan, Jiali Han, David E. Elder, Kevin M. Brown, Paola Ghiorzo, Peter A. Kanetsky, Mark A. Jenkins, Michelle M. van Rossum, Christian Ingvar, Simon N. Stacey, Ruth M. Pfeiffer, Gudmar Thorleifsson, Florence Demenais, Suzanne Mulder, Sancy A. Leachman, Tadeusz Dȩbniak, Judith Wendt, Maria Teresa Landi, Christopher I. Amos, Alisa M. Goldstein, Maria Del Pilar Royo Grasa, Valérie Chaudru, Patrick Sulem, Eitan Friedman, Shenying Fang, Rona M. MacKie, Dolores Planelles, Kari Stefansson, Rainer Tuominen, Nicholas K. Hayward, Nelleke A. Gruis, Anne C de Waal, Anne E. Cust, Julie Lang, Maria Concetta Fargnoli, Matthew Law, Per Helsing, Helen Snowden, Eduardo Nagore, Kristrun R. Benediktsdottir, Nicholas G. Martin, Qingyi Wei, Johan Hansson, Juliette Randerson-Moor, Esther Azizi, Hubert Pehamberger, Mario Santinami, Jan Lubinski, Marie-Françoise Avril, Jose I. Mayordomo, Jennifer H. Barrett, Monica Rodolfo, Licia Rivoltini, ProdInra, Migration, Haukeland University Hospital, University of Bergen (UiB), Queensland Institute of Medical Research, deCODE genetics [Reykjavik], Harvard University [Cambridge], Brigham and Women's Hospital [Boston], University of Texas Medical Branch, Partenaires INRAE, National Cancer Institute, St. James's University Hospital, Ctr Comprehens Canc, Radboud University [Nijmegen], Université Paris Descartes - Paris 5 (UPD5), Tel Aviv University (TAU), Leiden University, University of Iceland, Landspitali National University Hospital of Iceland, Università degli studi di Genova = University of Genoa (UniGe), San Martino Ist Sci Tumori, NCI, Maurizio Bufalini Hosp, Université d'Évry-Val-d'Essonne (UEVE), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Università degli Studi dell'Aquila = University of L'Aquila (UNIVAQ), University of Sydney, Sorbonne Paris Cite, Université Paris Diderot - Paris 7 (UPD7), Radboud University Medical Center [Nijmegen], Pomeranian Med Univ, PennState University, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), San Martino Ist Sci Tumori, Ist Ricovero & Cura Carattere Sci, Karolinska University Hospital [Stockholm], University of Oslo (UiO), Institute of Oncology Ljubljana, University of Melbourne, Dept Surg, Addenbrooke's Hospital, ServiceXS BV, Pennsylvania State University (Penn State), Penn State System, University of Glasgow, Ctr Natl Genotypage, Utah State University (USU), Dept Publ Hlth, Universiteit Gent = Ghent University (UGENT), New South Wales Government, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Instituto Valenciano de Oncologia, Medizinische Universität Wien = Medical University of Vienna, Lund University [Lund], Ctr Blood Transfus, Lab Histocompatibil Mol Biol, Universitat Autònoma de Barcelona (UAB), Instituto de Salud Carlos III [Madrid] (ISC), University of Barcelona, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Brigham and Women's Hospital, Tianjin Medical University Cancer Institute and Hospital, Leiden University Medical Center (LUMC), University of Texas, European Commission under the 6th Framework Programme [LSHC-CT-2006-018702], Cancer Research UK Programme Awards [C588/A4994 and C588/A10589], Cancer Research UK [C8216/A6129], Leeds Cancer Research UK Centre [C37059/A11941], US National Institutes of Health (NIH [CA83115], intramural Research Program of the NIH, US National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics, Wellcome Trust [076113], Swedish Cancer Society, Gunnar Nilsson Foundation, European Research Council [ERC-2011-AdG 294576], Italian Ministry of Education, University and Research Progetti di Ricerca di Interesse Nazionale [2008W8JTPA_002], Intergruppo Melanoma Italian, Mara Naum foundation, INCa [INCa-PL016], Ligue Nationale Contre Le Cancer [PRE05/ FD, PRE 09/FD], Programme Hospitaller de Recherche Clinique [AOM-07-195], European Biobanking and Biomolecular Resources Research Infrastructure Netherlands hub [C018], Fond de Investigaciones Sanitarias, Spain [P.I. 09/01393], Centro de Investigaciones Biomedicas en Red (CIBER), Comprehensive Cancer Center, Oslo University Hospital [SE0728], Norwegian Cancer Society [71512-PR-2006-0356], Jubilaumsfonds of the Osterreichische Nationalbank [12161, 13036], Hans und Blanca Moser Stiftung, NIH RO1 [CA65558-02], Department of Health and Human Services, Intramural Research Program of NIH, NCI Division of Cancer Epidemiology and Genetics, NIH NCI [CA83115, P30CA023108, 2P50CA093459, CA88363, CAl22838, CA87969, CA055075, CA100264, CA133996, CA49449], Marit Peterson Fund for Melanoma Research, Cancer Institute New South Wales, National Health and Medical Research Council, Dutch Cancer Society Koningin Wilhemina Fonds (KWF) Kankerbestrijding, Radboud University Medical Centre, Melanoma Research Alliance, National Health and Medical Research Council of Australia (NHMRC) [200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496675, 496739, 552485, 552498], Cancer Councils New South Wales, Victoria and Queensland, Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne), Australian Cancer Research Foundation, The Wellcome Trust [WT084766/Z/08/Z], NHMRC, Career Development award from the NHMRC [496674, 613705], Cancer Australia [1011143], Radboud university [Nijmegen], Tel Aviv University [Tel Aviv], University of Genoa (UNIGE), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Università degli Studi dell'Aquila () (Univaq), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universiteit Gent = Ghent University [Belgium] (UGENT), LeidenUniversity Medical Centre, Harvard University, Universiteit Leiden, University of Iceland [Reykjavik], and Institute of Oncology [Ljubljana]
Subjects: CUTANEOUS MELANOMA, [SDV]Life Sciences [q-bio], IDENTIFIES 3, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], FTO gene, Body Mass Index, 0302 clinical medicine, Risk Factors, ADULT OBESITY, Cooperative Behavior, 10. No inequality, Melanoma, Genetics, 0303 health sciences, Single Nucleotide, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Female, Settore MED/35 - MALATTIE CUTANEE E VENEREE, Genotype, SUSCEPTIBILITY LOCI, PREDISPOSES, PHENOTYPIC CHARACTERISTICS, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Meta-Analysis as Topic, Humans, Genetic Predisposition to Disease, Obesity, Polymorphism, Allele, GENOME-WIDE ASSOCIATION, METAANALYSIS, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Case-control study, Proteins, nutritional and metabolic diseases, Odds ratio, GENE, Auto-immunity, transplantation and immunotherapy Hereditary cancer and cancer-related syndromes [N4i 4], BODY-MASS INDEX, Genetic Loci, Case-Control Studies, Imputation (genetics), Genome-Wide Association Study
Abstract: Contains fulltext : 118658.pdf (Publisher’s version ) (Closed access) We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
Published: 2013

39. Differences in Transcription Patterns between Induced Pluripotent Stem Cells Produced from the Same Germ Layer Are Erased upon Differentiation

Author: Iryna Pirozhkova, Thomas Robert, Jörg Tost, Yegor S. Vassetzky, Gilles Carnac, Marc Lipinski, Elena S. Kim, Ana Barat, Dalila Laoudj-Chenivesse, Florence Busato, Petr Dmitriev, Justine Guegan, Chrystèle Bilhou-Nabera, Signalisation, noyaux et innovations en cancérologie (UMR8126), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Interactions moléculaires et cancer (IMC (UMR 8126)), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université de Paris (UP), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Passerieux, Emilie
Subjects: Cellular differentiation, Embryoid body, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Muscle Development, Myoblasts, Mice, 0302 clinical medicine, Molecular cell biology, Transduction, Genetic, Induced pluripotent stem cell, Cells, Cultured, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Multidisciplinary, Stem Cells, Cell Differentiation, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Stem cell, Cellular Types, Germ Layers, Research Article, Homeobox protein NANOG, KOSR, Science, Induced Pluripotent Stem Cells, DNA transcription, Kruppel-Like Transcription Factors, Biology, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Kruppel-Like Factor 4, SOX2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, Embryoid Bodies, Embryonic Stem Cells, 030304 developmental biology, Gene Expression Profiling, SOXB1 Transcription Factors, Mesenchymal Stem Cells, Fibroblasts, Molecular biology, Embryonic stem cell, Retroviridae, Gene expression, Octamer Transcription Factor-3, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Little is known about differences between induced pluripotent stem cells produced from tissues originating from the same germ layer. We have generated human myoblast-derived iPS cells by retroviral transduction of human primary myoblasts with the OCT3/4, SOX2, KLF4 and MYC coding sequences and compared them to iPS produced from human primary fibroblasts. When cultivated in vitro, these iPS cells proved similar to human embryonic stem cells in terms of morphology, expression of embryonic stemness markers and gene promoter methylation patterns. Embryonic bodies were derived that expressed endodermal, mesodermal as well as ectodermal markers. A comparative analysis of transcription patterns revealed significant differences in the gene expression pattern between myoblast-and fibroblast-derived iPS cells. However, these differences were reduced in the mesenchymal stem cells derived from the two iPS cell types were compared. Citation: Pirozhkova I, Barat A, Dmitriev P, Kim E, Robert T, et al. (2013) Differences in Transcription Patterns between Induced Pluripotent Stem Cells Produced from the Same Germ Layer Are Erased upon Differentiation.
Published: 2013

40. The Gene Coding for Interferon-γ Is Linked to the D12S335 and D12S313 Microsatellites and to the MDM2 Gene

Author: D. Le Paslier, Michel Brahic, Jean-François Bureau, Franck Bihl, Virus Lents, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Genetic Linkage, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Locus (genetics), Biology, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, Genetic linkage, Proto-Oncogene Proteins, Genetics, Animals, Humans, Gene, 030304 developmental biology, Synteny, 0303 health sciences, Chromosomes, Human, Pair 12, Base Sequence, Chromosome Mapping, Nuclear Proteins, Chromosome, Proto-Oncogene Proteins c-mdm2, 3. Good health, Chromosome Band, 030220 oncology & carcinogenesis, Human genome
Abstract: International audience; Interferon-gamma is a cytokine with multiple effects. It interferes with the replication of several viruses and plays a key role in the regulation of immune responses. Therefore, the gene coding for interferon-gamma could be implicated in the susceptibility of humans to several diseases. We have localized this gene close to the D12S335 and D12S313 microsatellites on both the physical and the genetic maps of the human genome. We also physically mapped this gene close to the MDM2 locus on chromosome band 12q15. Finally, we describe the organization of the Ifg, Myf-6, Mdm1, and Mdm2 loci on mouse chromosome 10, in a region syntenic to human chromosome band 12q15.
Published: 1995

41. Genome-wide association study of lung function decline in adults with and without asthma

Author: Ivan Curjuric, Kari E. North, Nicole Probst-Hensch, Nora Franceschini, Rachel Nadif, Matthias Wjst, Stefano Guerra, George T. O'Connor, Francine Kauffmann, Adaikalavan Ramasamy, Deborah Jarvis, Jemma B. Wilk, Florent Monier, Medea Imboden, David P. Strachan, Ashok Kumar, Emmanuelle Bouzigon, Manolis Kogevinas, Dirkje S. Postma, Florian Kronenberg, Judith M. Vonk, Gerard H. Koppelman, Mark Lathrop, Florence Demenais, Miriam F. Moffatt, Janine Altmüller, Laura R. Loehr, Joachim Heinrich, Valérie Siroux, Christian Schindler, Juan R. González, Stephanie J. London, Gian Andri Thun, Dana B. Hancock, Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Epidemiology & Public Health, Swiss Tropical and Public Health Institute [Basel]-Medical School University of Basel, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Department of Health and Human Services, National Institutes of Health [Bethesda] (NIH), Behavioral Health Epidemiology Program, Research Triangle Institute International (RTI International), Departments of Neurology and Medicine, Boston University School of Medicine (BUSM), Boston University [Boston] (BU)-Boston University [Boston] (BU)-Pulmonary Center, Department of Medicine, Pediatric Pulmonology, Allergology & Epidemiology, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG)-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, IMIM-Hospital del Mar, Generalitat de Catalunya, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Cologne Center for Genomics (CCG), Cologne Center for Genomics-University of Cologne, Arizona Respiratory Center, Division of genetic epidemiology, Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, National Heart and Lung Institute (NHLI), Imperial College London, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Population Health Sciences and Education, St George's University of London, Epidemiology, National School of Public Health-Medical School of Athens, EGEA: INSERM-Ministry of Research 'Cohortes et Collections' grant (4CH06G). French Ministry of Higher Education and Research, University Paris Diderot-Paris 7, grants from the French Agency for Environmental and Occupational Health Safety (grant AFSSETAPR- SE-2004), the French National Agency for Research (grants ANR 05- SEST-020- 02/05-9-97 and ANR 06-CEBS), PHRC-Paris, Merck Sharp & Dohme (MSD)) SAPALDIA: Swiss National Science Foundation (grants no 4026-28099,3347CO- 108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 32-65896.01,32- 59302.99, 32-52720.97, 32-4253.94), the Federal Office for Forest, Environment and Landscape, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Zurich, the Swiss Lung League, the canton's Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino and Zurich, Freie Akademische Gesellschaft (FAG), UBS Wealth Foundation. ECRHS: The co-ordination of ECRHS II was supported by the European Commission, as part of their Quality of Life programme. The following bodies funded the local studies in ECRHS II: Albacete: Fondo de Investigaciones Santarias (FIS) (grant code: 97/0035-01, 99/0034-01 and 99/0034-02), Hospital Universitario de Albacete, Consejeria de Sanidad, Barcelona: SEPAR, Public Health Service (grant code: R01 HL62633-01), Fondo de Investigaciones Santarias (FIS) (grant code: 97/0035-01, 99/0034-01 and 99/0034-02) CIRIT (grant code: 1999SGR 00241) Red Respira ISCII, CIBER Epidemiologia y Salud Pública (CIBERESP), Spain Basel: Swiss National Science Foundation, Swiss Federal Office for Education & Science, Swiss National Accident Insurance Fund (SUVA), USC NIEHS Center grant 5P30 ES07048, Bergen: Norwegian Research Council, Norwegian Asthma & Allergy Association (NAAF), Glaxo Wellcome AS, Norway Research Fund, Erfurt: GSF-National Research Centre for Environment & Health, Deutsche Forschungsgemeinschaft (DFG) (grant code FR 1526/1-1), Galdakao: Basque Health Dept, Grenoble: Programme Hospitalier de Recherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche Clinique, CHU de Grenoble, Ministere de l'Emploi et de la Solidarite, Direction Generale de la Sante, Comite des Maladies Respiratoires de l'Isere, Hamburg: GSF-National Reasearch Centre for Environment & Health, Deutsche Forschungsgemeinschaft (DFG) (grant code MA 711/4-1), Ipswich and Norwich: Asthma UK (formerly known as National Asthma Campaign), Huelva: Fondo de Investigaciones Santarias (FIS) (grant code: 97/0035-01, 99/0034-01 and 99/0034-02), Oviedo: Fondo de Investigaciones Santarias (FIS) (grant code: 97/0035-01, 99/0034-01 and 99/0034-02), Paris: Ministere de l'Emploi et de la Solidarite, Direction Generale de la Sante, UCB-Pharma (France), Aventis (France), Glaxo France, Programme Hospitalier de Recherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche Clinique, CHU de Grenoble, Tartu: Estonian Science Foundation, Umeå: Swedish Heart Lung Foundation, Swedish Foundation for Health Care Sciences & Allergy Research, Swedish Asthma & Allergy Foundation, Swedish Cancer & Allergy Foundation, Uppsala: Swedish Heart Lung Foundation, Swedish Foundation for Health Care Sciences & Allergy Research, Swedish Asthma & Allergy Foundation, Swedish Cancer & Allergy Foundation, Financial support for ECRHS I for centres in ECRHS II was provided by: Ministère de la Santé, Glaxo France, Insitut Pneumologique d'Aquitaine, Contrat de Plan Etat-Région Languedoc-Rousillon, CNMATS, CNMRT (90MR/10, 91AF/6), Ministre delegué de la santé, RNSP, France, GSF, and the Bundesminister für Forschung und Technologie, Bonn, Germany, Norwegian Research Council project no. 101422/310, Ministero Sanidad y Consumo FIS (grants #91/0016060/00E-05E and #93/0393), and grants from Hospital General de Albacete, Hospital General Juan Ramón Jiménenz, Consejeria de Sanidad Principado de Asturias, Spain, The Swedish Medical Research Council, the Swedish Heart Lung Foundation, the Swedish Association against Asthma and Allergy, Swiss National Science Foundation grant 4026-28099, National Asthma Campaign, British Lung Foundation, Department of Health, South Thames Regional Health Authority, UK. A.R. was supported by the Department of Health, UK and the European Commission as part of GABRIEL contract number 018996 under the Integrated Program LSH-2004-1.2.5-1. Genotyping of the discovery cohort and part of B58C was funded by the GABRIEL asthma genetic consortium supported by a contract from the European Commission(018996) and grants from the French Ministry of Research, the Wellcome Trust (WT084703MA), and Asthma UK. Replication cohorts: ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Work for this manuscript was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS, Z01ES043012). FHS: National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). Dr. Wilk by a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. B58C: British 1958 Birth Cohort was funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). Genotyping was funded by the Wellcome Trust grant 076113/B/04/Z, by the United States National Institutes of Health and the Juvenile Diabetes Research Foundation U01 DK062418 and by the European Commission Framework Programme 6 (018996). Dutch Asthma Study: The Dutch Asthma study has been funded by the Netherlands Asthma Foundation grants AF 3.2.07.015, and AF 98.48 and a grant from the University Medical Center Groningen, Nadif, Rachel, University of Oxford, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Male, Vital capacity, MESH: Asthma, Vital Capacity, LOCI, Genome-wide association study, CHILDREN, VARIANTS, 0302 clinical medicine, Framingham Heart Study, S-TRANSFERASE M1, cohort studies, Forced Expiratory Volume, Immunology and Allergy, Lung, GENERAL-POPULATION, 0303 health sciences, COPD, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Respiratory disease, LARGE-SCALE, MESH: Follow-Up Studies, Middle Aged, respiratory system, 3. Good health, Neoplasm Proteins, Europe, MESH: Young Adult, Female, MESH: Membrane Proteins, Cohort study, Adult, CANDIDATE GENE, medicine.medical_specialty, Immunology, PHENOTYPES, MESH: Forced Expiratory Volume, Polymorphism, Single Nucleotide, OBSTRUCTIVE PULMONARY-DISEASE, Article, 03 medical and health sciences, FEV1/FVC ratio, Young Adult, Internal medicine, medicine, Humans, MESH: Tumor Suppressor Proteins, MESH: Lung, POLYMORPHISMS, 030304 developmental biology, Asthma, MESH: Humans, Chromosomes, Human, Pair 13, business.industry, Tumor Suppressor Proteins, lung function decline, Membrane Proteins, MESH: Adult, MESH: Vital Capacity, medicine.disease, MESH: Male, respiratory tract diseases, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Genome-Wide Association Study, genome-wide association, MESH: Chromosomes, Human, Pair 13, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Europe, heterogeneity, business, MESH: Female, Follow-Up Studies, Genome-Wide Association Study
Abstract: Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function.Objective: We conducted the first genome-wide association study on the age-related decrease in FEV1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status.Methods: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV1 and FEV1/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study).Results: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 x 10(-6); replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV1/FVC ratio decrease in asthmatic participants (P = 5.3 x 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline.Conclusions: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status. (J Allergy Clin Immunol 2012;129:1218-28.)
Published: 2012

42. Transient receptor potential genes, smoking, occupational exposures and cough in adults

Author: Nicole Le Moual, Emmanuelle Bouzigon, Deborah Jarvis, Miguel A. Valverde, Juan R. González, Isabelle Pin, Joachim Heinrich, Florence Demenais, Josep M. Antó, Manolis Kogevinas, Anne-Elie Carsin, Hans Kromhout, Roel Vermeulen, Mark Lathrop, Lidwien A.M. Smit, Christer Janson, Francine Kauffmann, Ivo Gut, Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, IMIM-Hospital del Mar, Generalitat de Catalunya, CIBER Epidemiologia y Salud Pública (CIBERESP), CIBER de Epidemiología y Salud Pública (CIBERESP), Epidemiology, National School of Public Health-Medical School of Athens, Department of Experimental and Health Sciences, Universitat Pompeu Fabra [Barcelona] (UPF), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pédiatrie, CHU Grenoble-Hôpital Michallon, Respiratory Epidemiology and Public Health Group, Imperial College London-National Heart and Lung Institute [UK], Department of Medical Sciences: Respiratory Medicine and Allergology, Uppsala University, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Molecular Physiology and Channelopathies, The EGEA study was funded by INSERM, grants from the French Agency for Environmental and Occupational Health Safety (grant AFSSET-APR-SE-2004), the French National Agency for Research (grants ANR 05-SEST-020-02/05-9- 97, ANR 06-CEBS and ANR 10-PRSP) and Merck Sharp & Dohme (MSD). Regarding ECRHS II, the coordination was supported by the European Commission, as part of their Quality of Life programme., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, and BMC, Ed.
Subjects: Male, Medicin och hälsovetenskap, Pharmacology, Medical and Health Sciences, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Epidemiologia genètica, Transient Receptor Potential Channels, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Epidemiology, Irritant exposure, TRP channel, Medicine, TRPA1 Cation Channel, 0303 health sciences, Smoking, Middle Aged, 3. Good health, Europe, Chronic cough, Female, France, medicine.symptom, Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, TRPV Cation Channels, Nerve Tissue Proteins, Single-nucleotide polymorphism, Asthma, Gene-environment interaction, Polymorphism, Single Nucleotide, 03 medical and health sciences, Occupational Exposure, Internal medicine, Humans, SNP, Genetic Predisposition to Disease, Tabac -- Efectes fisiològics, 030304 developmental biology, Genetic association, lcsh:RC705-779, business.industry, Research, Haplotype, Case-control study, Asma -- Epidemiologia, lcsh:Diseases of the respiratory system, medicine.disease, Health Surveys, respiratory tract diseases, Cough, Haplotypes, 030228 respiratory system, Case-Control Studies, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Calcium Channels, business
Abstract: Background: Transient receptor potential (TRP) vanilloid and ankyrin cation channels are activated by various noxious chemicals and may play an important role in the pathogenesis of cough. The aim was to study the influence of single nucleotide polymorphisms (SNPs) in TRP genes and irritant exposures on cough. Methods: Nocturnal, usual, and chronic cough, smoking, and job history were obtained by questionnaire in 844 asthmatic and 2046 non-asthmatic adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Occupational exposures to vapors, gases, dusts, and/or fumes were assessed by a job-exposure matrix. Fifty-eight tagging SNPs in TRPV1, TRPV4, and TRPA1 were tested under an additive model. Results: Statistically significant associations of 6 TRPV1 SNPs with cough symptoms were found in non-asthmatics after correction for multiple comparisons. Results were consistent across the eight countries examined. Haplotype-based association analysis confirmed the single SNP analyses for nocturnal cough (7-SNP haplotype: p-global = 4.8 × 10-6) and usual cough (9-SNP haplotype: p-global = 4.5 × 10-6). Cough symptoms were associated with exposure to irritants such as cigarette smoke and occupational exposures (p < 0.05). Four polymorphisms in TRPV1 further increased the risk of cough symptoms from irritant exposures in asthmatics and non-asthmatics (interaction p < 0.05). Conclusions: TRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries. TRPV1 SNPs may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures. The EGEA study was funded by INSERM, grants from the French Agency for Environmental and Occupational Health Safety (grant AFSSET-APR-SE-2004), the French National Agency for Research (grants ANR 05-SEST-020-02/05-9-97, ANR 06-CEBS and ANR 10-PRSP) and Merck Sharp & Dohme (MSD)
Published: 2012

43. Associations between nitric oxide synthase genes and exhaled NO-related phenotypes according to asthma status

Author: Mekki Boussaha, Emmanuelle Bouzigon, Florent Monier, Régis Matran, Hélène Huyvaert, Rachel Nadif, Mark Lathrop, Jean Bousquet, Florence Demenais, Francine Kauffmann, Sébastien Letort, Isabelle Pin, Nicole Le Moual, Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service d'explorations fonctionnelles respiratoires [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pédiatrie, CHU Grenoble-Hôpital Michallon, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), This research is funded in part by PHRC-Paris, PHRC-Grenoble, ANR 05-SEST-020-02/05-9-97, ANR-06-CEBS, ANR-CES-2009, Region Nord Pas-de-Calais, Merck Sharp & Dohme (MSD), the GA2LEN project, Global Allergy and Asthma European Network and GABRIEL, a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community (contract 018996 from the European Commission)., the EGEA Cooperative Group, Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and Nadif, Rachel
Subjects: Male, Pulmonology, MESH: Asthma, Epidemiology, lcsh:Medicine, Biochemistry, 0302 clinical medicine, Pathology, Exhaled breath condensate, lcsh:Science, 0303 health sciences, Multidisciplinary, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, Neurochemistry, respiratory system, Middle Aged, 3. Good health, Phenotype, Breath Tests, Genetic Epidemiology, Medicine, Female, MESH: Nitric Oxide Synthase, Neurochemicals, Research Article, Adult, NOS1, Single-nucleotide polymorphism, Biology, Nitric Oxide, MESH: Phenotype, Polymorphism, Single Nucleotide, 03 medical and health sciences, Diagnostic Medicine, Genetics, medicine, Humans, SNP, Allele, 030304 developmental biology, Asthma, Evolutionary Biology, MESH: Humans, Population Biology, Genetic heterogeneity, lcsh:R, Computational Biology, MESH: Adult, medicine.disease, MESH: Male, respiratory tract diseases, MESH: Breath Tests, 030228 respiratory system, Genetic epidemiology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Nitric Oxide, Immunology, Genetic Polymorphism, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lcsh:Q, Nitric Oxide Synthase, MESH: Female, Population Genetics, Biomarkers, Neuroscience, General Pathology
Abstract: International audience; BACKGROUND: The nitric oxide (NO) pathway is involved in asthma, and eosinophils participate in the regulation of the NO pool in pulmonary tissues. We investigated associations between single nucleotide polymorphisms (SNPs) of NO synthase genes (NOS) and biological NO-related phenotypes measured in two compartments (exhaled breath condensate and plasma) and blood eosinophil counts. METHODOLOGY: SNPs (N = 121) belonging to NOS1, NOS2 and NOS3 genes were genotyped in 1277 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA). Association analyses were conducted on four quantitative phenotypes: the exhaled fraction of NO (Fe(NO)), plasma and exhaled breath condensate (EBC) nitrite-nitrate levels (NO2-NO3) and blood eosinophils in asthmatics and non-asthmatics separately. Genetic heterogeneity of these phenotypes between asthmatics and non-asthmatics was also investigated. PRINCIPAL FINDINGS: In non-asthmatics, after correction for multiple comparisons, we found significant associations of Fe(NO) levels with three SNPs in NOS3 and NOS2 (P ≤ 0.002), and of EBC NO2-NO3 level with NOS2 (P = 0.002). In asthmatics, a single significant association was detected between Fe(NO) levels and one SNP in NOS3 (P = 0.004). Moreover, there was significant heterogeneity of NOS3 SNP effect on Fe(NO) between asthmatics and non-asthmatics (P = 0.0002 to 0.005). No significant association was found between any SNP and NO2-NO3 plasma levels or blood eosinophil counts. CONCLUSIONS: Variants in NO synthase genes influence Fe(NO) and EBC NO2-NO3 levels in adults. These genetic determinants differ according to asthma status. Significant associations were only detected for exhaled phenotypes, highlighting the critical relevance to have access to specific phenotypes measured in relevant biological fluid.
Published: 2012

44. Construction of a YAC contig and a STS map spanning at least seven megabasepairs in chromosome 5q34-35

Author: Danlel Cohen, llya Chumakov, Jean Welssenbach, Jennifer Lu-Kuo, Denis Le Pasller, David C. Ward, Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Genetic Markers, congenital, hereditary, and neonatal diseases and abnormalities, Molecular Sequence Data, Translocation Breakpoint, DNA, Satellite, Biology, Polymerase Chain Reaction, Translocation, Genetic, Cell Line, Sequence-tagged site, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, hemic and lymphatic diseases, Genetics, Humans, Chromosomes, Artificial, Yeast, Interphase, Molecular Biology, In Situ Hybridization, In Situ Hybridization, Fluorescence, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), DNA Primers, 030304 developmental biology, Base Composition, 0303 health sciences, Polymorphism, Genetic, Base Sequence, Contig, Breakpoint, Chromosome Mapping, Chromosome, General Medicine, Cosmids, Molecular biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Chromosomes, Human, Pair 2, 030220 oncology & carcinogenesis, Cosmid, Chromosomes, Human, Pair 5, Microsatellite
Abstract: We have constructed a YAC contig containing 54 clones and a minimum of 7 Mbp of human DNA, that maps to bands q34 − 35 on chromosome 5. The contig was nucleated using FISH mapped cosmid clones shown to flank the t(2;5)(p23;q35) translocation breakpoint in a CD30-positive large cell lymphoma cell line. Thirty of the 54 YAC clones are non-chimeric and six span the translocation breakpoint, as determined by FISH analysis. A total of 28 YAC clone end fragments, 14 non-polymorphic YAC end STS probes and 13 polymorphic microsatellite STS markers have been used to order clones within the contig. The most distal genetic markers (D5S498 and D5S619) are separated by 15 cM based on multipoint linkage analysis. This map of overlapping clones and the set of densely spaced physical markers will promote our understanding of the 5q34 − 35 region and its associated genes
Published: 1994

45. Mold allergen sensitization in adult asthma according to integrin β3 polymorphisms and Toll-like receptor 2/+596 genotype

Author: Valérie Siroux, Emmanuelle Bouzigon, Mark Lathrop, Nicole Le Moual, Isabelle Pin, Francine Kauffmann, Rachel Nadif, Lidwien A.M. Smit, Jean Bousquet, Florence Demenais, Institute for Risk Assessment Sciences [Utrecht, The Netherlands] (IRAS), Utrecht University [Utrecht], Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Supported by the French Ministry of Higher Education and Research, University Paris Diderot-Paris 7, grants from the French Agency for Environmental and Occupational Health Safety (grant AFSSET-APR-SE-2004), the French National Agency for Research (grants ANR 05-SEST-020-02/05-9-97 and ANR 06-CEBS), Merck Sharp & Dohme (MSD), Hospital program of clinical research (PHRC)-Paris, and by the Netherlands Organisation for Scientific Research (NWO) Van Gogh Programme for French-Dutch cooperation. Lidwien Smit was supported by a European Academy of Allergology and Clinical Immunology-Global Allergy and Asthma European Network (EAACI-GA2LEN) exchange fellowship award, Epidemiological Study on the Genetics and Environment of Asthma, Nadif, Rachel, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), and Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset
Subjects: Male, epistasis, MESH: Integrin beta3, Allergy, Candidate gene, MESH: Asthma, Allergic sensitization, MESH: Genotype, 0302 clinical medicine, Genotype, Immunology and Allergy, genetics, innate immunity, Sensitization, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, Integrin beta3, MESH: Genetic Predisposition to Disease, Alternaria, MESH: Toll-Like Receptor 2, 3. Good health, medicine.anatomical_structure, Aspergillus, Female, epidemiology, Cladosporium, Adult, MESH: Fungi, MESH: Allergens, MESH: Hypersensitivity, Immunology, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genetic model, medicine, Hypersensitivity, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Asthma, MESH: Humans, Fungi, MESH: Adult, Allergens, asthma, medicine.disease, allergy, Toll-Like Receptor 2, MESH: Male, respiratory tract diseases, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female
Abstract: International audience; BACKGROUND: Integrin β3 (ITGB3) and Toll-like receptor 2 (TLR2) are candidate genes for asthma and sensitization to mold allergens. Integrin β3 forms a complex with TLR2, and this biological interaction is required for the response of monocytes to TLR2 agonists such as fungal glucan. OBJECTIVE: To study whether genetic interaction between single nucleotide polymorphisms (SNPs) in genes encoding the TLR2-ITGB3 complex enhances susceptibility to mold sensitization. METHODS: Association analysis was conducted in 1243 adults (524 with asthma) who participated in the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma. Allergic sensitization to mold allergens was determined by skin prick testing. Association of mold sensitization with 14 ITGB3 SNPs was tested under an additive genetic model. Interaction between ITGB3 SNPs and TLR2/+596, which was previously shown to be associated with asthma, was studied. RESULTS: A positive skin prick test to mold was found in 115 subjects with asthma (22.0%) and in 61 subjects without asthma (8.5%). The ITGB3 rs2056131 A allele was associated with mold sensitization in subjects with asthma with an odds ratio (95% CI) of 0.60 (0.43-0.83; P = .001). Ten other ITGB3 SNPs were significantly associated with mold sensitization in TLR2/+596TT subjects with asthma (P = .03-.002), whereas much weaker associations were found in carriers of the TLR2/+596 C allele (P = .60-.04). Interaction between TLR2/+596 and these ITGB3 SNPs was statistically significant (P interaction = .05-.001). CONCLUSION: TLR2/+596 genotype may influence the association between ITGB3 SNPs and mold sensitization in adults with asthma.
Published: 2011

46. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping

Author: C. Ben Hamida, N. Doerflinger, S. Belal, C. Linder, L. Reutenauer, C. Dib, G. Gyapay, A. Vignal, D. Le Paslier, D. Cohen, M. Pandolfo, V. Mokini, G. Novelli, F. Hentati, M. Ben Hamida, J.-L. Mandel, M. Kœnig, Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Adult, Male, Yeast artificial chromosome, Tunisia, Ataxia, Genetic Linkage, Locus (genetics), Biology, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Genetics, medicine, Humans, Vitamin E Deficiency, Chromosomes, Artificial, Yeast, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Contig, Homozygote, Haplotype, Chromosome Mapping, Middle Aged, Disease gene identification, Pedigree, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Haplotypes, Friedreich Ataxia, Female, Vitamin E deficiency, medicine.symptom, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 8
Abstract: Friedreich ataxia and ataxia with selective vitamin E deficiency (AVED) share very similar clinical phenotypes. We have mapped the AVED locus to proximal 8q with only three large consanguinous Tunisian families, representing to our knowledge the first use of homozygosity mapping for primary linkage analysis. Subsequently, three additional families showed linkage with the same markers. A maximum lod score of 17.9 was obtained at theta = 0 for the haplotype D8S260-D8S510, consisting of the two closest markers. With only 6 families, the AVED locus is therefore mapped precisely as illustrated by the lod-1 confidence interval of 2.4 cM on either side of D8S260-D8S510. Isolation of a yeast artificial chromosome contig > 800 kilobases (kb) showed that D8S260 and D8S510 are less than 400 kb apart.
Published: 1993

47. European collaborative study of early-onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

Author: Mathieu, Flavie, Dizier, Marie-Hélène, Etain, Bruno, Jamain, Stéphane, Rietschel, Marcella, Maier, Wolfgang, Albus, Margot, Mckeon, Patrick, Roche, Siobhan, Blackwood, Douglas, Muir, Walter, Henry, Chantal, Malafosse, Alain, Preisig, Martin, Ferrero, François, Cichon, Sven, Schumacher, Johannes, Ohlraun, Stephanie, Propping, Peter, Abou Jamra, Rami, Schulze, Thomas, Zelenica, Diana, Charon, Céline, Marusic, Andrej, Dernovsek, Mojca, Gurling, Hugh, Nöthen, Markus, Lathrop, Mark, Leboyer, Marion, Bellivier, Frank, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Fondation FondaMental [Créteil], Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Department of Psychiatry, Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Psychiatry and Psychotherapy, District Hospital Haar, St. Patrick's Hospital, Smurfit Institute of Genetics, Trinity College Dublin, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Urgence et post-urgence psychiatrique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Department of psychiatry, University Hospital - Lausanne, Geneva University Hospital (HUG), Center for Human Genetic Research, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Institute of Human Genetics, Georg-August-University [Göttingen], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute of Public Health of the Republic of Slovenia, University Psychiatric Hospital, Department of psychiatry and behavioural Sciences, Windeyer Institute for Medical Sciences-Royal Free and University College London Medical School, Grant sponsor: INSERM, Grant sponsor: Assistance Publique des Hôpitaux de Paris, Grant sponsor: Agence Nationale pour la Recherche (ANR-Project Manage-BP), Grant sponsor: National Alliance for Research on Schizophrenia and Depression (NARSAD), Grant sponsor: Fondation pour la Recherche sur le Cerveau (FRC), Grant sponsor: RTRS Santé Mentale (FondaMental), Grant sponsor: National Genomic Network (NGFN) of the German Ministry of Education and Research, Grant sponsor: Deutsche Forschungsgemeinschaft (SFB 400 Subprojects D1 and D3, Graduiertenkolleg GRK 246, FOR 423 Subproject D1), Grant sponsor: Alfried Krupp von Bohlen und Halbach-Stiftung, Grant sponsor: Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy Office, Grant sponsor: German Research Society (Grant Numbers: AL 230-1/2/3-230-5/1/2, SFB 400), Grant sponsor: Aware, Grant sponsor: Health Research Board (Grant Number: H01069 HRB RP153/2000), Grant sponsor: Friends of St. Patrick‟s Hospital, and Grant sponsor: Swiss National Foundation ( Grant Numbers: 32-40677.94, 32-47315.96, 32-061974.00, 32-66793.01, 32-102168.03).
Subjects: MESH: Adolescent, MESH: Humans, Bipolar disorder, MESH: Age of Onset, MESH: Genetic Linkage, MESH: Genetic Predisposition to Disease, MESH: Chromosomes, Human, Pair 2, MESH: Genetic Heterogeneity, MESH: Genetic Markers, MESH: Male, genetic heterogeneity, MESH: Genotype, MESH: Young Adult, MESH: Bipolar Disorder, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Europe, MESH: Chromosome Mapping, age at onset, MESH: Data Interpretation, Statistical, MESH: Female, MESH: Genetic Association Studies
Abstract: International audience; Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms. © 2010 Wiley-Liss, Inc.
Published: 2010

48. Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

Author: Bouzigon, Emmanuelle, Forabosco, Paola, Koppelman, Gerard, Cookson, William, Dizier, Marie-Hélène, Duffy, David, Evans, David, Ferreira, Manuel, Kere, Juha, Laitinen, Tarja, Malerba, Giovanni, Meyers, Deborah, Moffatt, Miriam, Martin, Nicholas, Ng, Mandy, Pignatti, Pier Franco, Wjst, Mathias, Kauffmann, Francine, Demenais, Florence, Lewis, Cathryn, Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical and Molecular Genetics, King‘s College London, Istituto di Genetica delle Popolazioni-CNR, Consiglio Nazionale delle Ricerche (CNR), Department of Pulmonary Medicine and Tuberculosis, University of Groningen [Groningen], National Heart and Lung Institute (NHLI), Imperial College London, Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Queensland Institute of Medical Research, Department of Social Medicine, University of Bristol [Bristol], Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Departments of Pulmonary Medicine and Medical Genetics, Section of Biology & Genetics, University of Verona (UNIVR), Center for Human Genomics, Wake Forest University, MRC SGDP Centre, Institute of Experimental Pneumology, Helmholtz-Zentrum München (HZM), Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), and This study was supported by the European Commission as part of the GA2LEN project, Global Allergy and Asthma European Network (contract no. FOOD-CT-2004-506378) and GABRIEL, a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community (contract no. 01896 under the Integrated Programme LSH-2004-1.2.5-1
Subjects: MESH: Humans, MESH: Asthma, MESH: Eosinophils, MESH: Genome-Wide Association Study, MESH: Immunoglobulin E, MESH: Genetic Heterogeneity, MESH: Genetic Linkage, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Hypersensitivity, Immediate, MESH: Blood Cell Count, MESH: Phenotype, MESH: Chromosome Mapping
Abstract: International audience; Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (>or=3024 families with >or=10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21-p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3-q24 in all families for SPT and three other regions in European families (2q32-q34 for EOS, 5q23-q33 for SPTQ and 17q12-q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11-3q21, whereas between-study heterogeneity was detected for asthma in 2p22-p13 and 6p21, and for atopic asthma in 1q23-q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies.
Published: 2010

49. A large-scale, consortium-based genomewide association study of asthma

Author: Maxim Freydin, Göran Pershagen, Florence Demenais, Torben Sigsgaard, Ashish Kumar, Jennie Hui, Juha Kere, Erika Von Mutius, Inger Kull, Robert Niven, Fredrik Nyberg, John Beilby, Inge M. Wouters, Benedicte Leynaert, Ian Sayers, Aristea Binia, Jon Genuneit, Maria Solodilova, Peter Burney, Angela Simpson, Dick Heederik, Vivi Schlünssen, Marie-Hélène Dizier, David Balding, Ioannis Basinas, Alexandra Karunas, Olga Kobyakova, Karl Franklin, Lyle John Palmer, Deborah Jarvis, Yuliya Fedorova, John Holloway, Mona Bafadhel, Elza Khusnutdinova, Roel Vermeulen, Joachim Heinrich, Landsteiner Laboratory, National Heart and Lung Institute (NHLI), Imperial College London, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Population Health Sciences and Education, St George's University of London, Asthma and Allergy Department, University Children's Hospital-Ludwig-Maximilians University [Munich] (LMU), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, This work was supported by the European Commission as part of GABRIEL (A multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community) contract number 018996 under the Integrated Program LSH-‐2004-‐1.2.5-‐1. The study was also funded by the Wellcome Trust under WT084703MA: 'A second-‐generation genome-‐wide association study for asthma', and Asthma UK (the Asthma UK genetics of severe asthma study (AUGOSA))., for the GABRIEL Consortium, University Children's Hospital-Ludwig Maximilians University, University of Oxford [Oxford], and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: Male, MESH: Asthma, IL1RL1, Genome-wide association study, MESH: Logistic Models, VARIANTS, DISEASE, 0302 clinical medicine, MESH: Child, Odds Ratio, Chromosomes, Human, Susceptibility Gene, Positional cloning, In-vivo, Variants, Disease, Expression, Cytokine, Receptor, Allergy, Traits, Age of Onset, Child, IN-VIVO, Genetics, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH: Immunoglobulin E, MESH: Genetic Predisposition to Disease, General Medicine, MESH: Case-Control Studies, 3. Good health, ALLERGY, Occupational Diseases, SUSCEPTIBILITY GENE, Female, Occupational asthma, TRAITS, POSITIONAL CLONING, EXPRESSION, MESH: Occupational Diseases, Adolescent, MESH: Hypersensitivity, MESH: Age of Onset, Chromosome 9, MESH: Chromosomes, Human, MESH: Genetic Loci, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Chromosome 15, Th2 Cells, MESH: Th2 Cells, medicine, Hypersensitivity, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Asthma, MESH: Adolescent, MESH: Humans, RECEPTOR, business.industry, HLA-DR Antigens, Immunoglobulin E, medicine.disease, MESH: HLA-DR Antigens, MESH: Male, MESH: Odds Ratio, CYTOKINE, Logistic Models, 030228 respiratory system, Genetic Loci, Case-Control Studies, Immunology, MESH: Genome-Wide Association Study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Chromosome 22, MESH: Female, Genome-Wide Association Study
Abstract: BACKGROUND: Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. METHODS: We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. RESULTS: We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3×10(−9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7×10(−14)); rs1342326 on chromosome 9, flanking IL33 (P=9×10(−10)); rs744910 on chromosome 15 in SMAD3 (P=4×10(−9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1×10(−8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6×10(−23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. CONCLUSIONS: Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)
Published: 2010

50. Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

Author: Francine Kauffmann, M. Wjst, Miriam F. Moffatt, Manuel A. R. Ferreira, Tarja Laitinen, Gerard H. Koppelman, Giovanni Malerba, Emmanuelle Bouzigon, William O.C.M. Cookson, Deborah A. Meyers, Florence Demenais, David L. Duffy, Nicholas G. Martin, Cathryn M. Lewis, Juha Kere, Mandy Y.M. Ng, Pier Franco Pignatti, Paola Forabosco, David M. Evans, Marie-Hélène Dizier, Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical and Molecular Genetics, King‘s College London, Istituto di Genetica delle Popolazioni-CNR, Consiglio Nazionale delle Ricerche (CNR), Department of Pulmonary Medicine and Tuberculosis, University of Groningen [Groningen], National Heart and Lung Institute (NHLI), Imperial College London, Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Queensland Institute of Medical Research, Department of Social Medicine, University of Bristol [Bristol], Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Departments of Pulmonary Medicine and Medical Genetics, Section of Biology & Genetics, University of Verona (UNIVR), Center for Human Genomics, Wake Forest University, MRC SGDP Centre, Institute of Experimental Pneumology, Helmholtz-Zentrum München (HZM), Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was supported by the European Commission as part of the GA2LEN project, Global Allergy and Asthma European Network (contract no. FOOD-CT-2004-506378) and GABRIEL, a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community (contract no. 01896 under the Integrated Programme LSH-2004-1.2.5-1, Faculteit Medische Wetenschappen/UMCG, and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: Hypersensitivity, Immediate, Asthma, Atopy, Meta-analysis, Linkage scan, Allergy, MESH: Asthma, Genetic Linkage, atopy, Genome-wide association study, FAMILIES, meta-analysis, genome-wide linkage, asthma, 0302 clinical medicine, MESH: Blood Cell Count, COSTA-RICA, Genetics (clinical), Genetics, 0303 health sciences, biology, MESH: Immunoglobulin E, MESH: Genetic Heterogeneity, Chromosome Mapping, 3. Good health, SUSCEPTIBILITY GENES, Phenotype, SMOKING EXPOSURE, BRONCHIAL HYPERRESPONSIVENESS, MESH: Hypersensitivity, Immediate, linkage scan, MESH: Genetic Linkage, Context (language use), MESH: Phenotype, Article, FOUNDER POPULATION, 03 medical and health sciences, Genetic Heterogeneity, MESH: Eosinophils, medicine, Humans, SERUM IMMUNOGLOBULIN-E, 030304 developmental biology, Genetic association, House dust mite, MESH: Humans, Genetic heterogeneity, PULMONARY-FUNCTION, CHILDHOOD ASTHMA, SEARCH METAANALYSIS, Immunoglobulin E, medicine.disease, biology.organism_classification, Blood Cell Count, Eosinophils, 030228 respiratory system, MESH: Genome-Wide Association Study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Chromosome Mapping, Genome-Wide Association Study
Abstract: Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (>= 3024 families with >= 10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21-p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3-q24 in all families for SPT and three other regions in European families (2q32-q34 for EOS, 5q23-q33 for SPTQ and 17q12-q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11-3q21, whereas between-study heterogeneity was detected for asthma in 2p22-p13 and 6p21, and for atopic asthma in 1q23-q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies. European Journal of Human Genetics (2010) 18, 700-706; doi: 10.1038/ejhg.2009.224; published online 13 January 2010
Published: 2010

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