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1. FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype‐phenotype correlations

Author: Ader, Flavie, De Groote, Pascal, Réant, Patricia, Rooryck-Thambo, Caroline, Dupin-Deguine, Delphine, Rambaud, Caroline, Khraiche, Diala, Perret, Claire, Pruny, Jean François, Mathieu-Dramard, Michele, Gérard, Marion, Troadec, Yann, Gouya, Laurent, Jeunemaitre, Xavier, Van Maldergem, Lionel, Hagège, Albert, Villard, Eric, Charron, Philippe, Richard, Pascale, Rooryck‐Thambo, Caroline, Dupin‐Deguine, Delphine, Mathieu‐Dramard, Michèle, 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), Sorbonne Université (SU), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Biochimie Métabolique [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), Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Adaptation cardiovasculaire à l'ischemie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Stress Abiotiques et Différenciation des Végétaux Cultivés (SADV), Université de Lille, Sciences et Technologies-Institut National de la Recherche Agronomique (INRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Service de Génétique [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), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Therapie Cellulaire en Pathologie Cardio-Vasculaire (UMR_S 633), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), gerard, marion, 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], Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Recherche Agronomique (INRA)-Université de Lille, Sciences et Technologies, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Montréal - UdeM (CANADA), Université de Montréal (UdeM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre de Génétique Moléculaire et Chromosomique du GH Pitié-Salpêtrière-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Département de cardiologie, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], Service d'Anatomie Pathologique et Médecine Légale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Raymond Poincaré [Garches], Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bichat, Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Paris - UFR Sciences Fondamentales et Biomédicales [Sciences], Université de Paris (UP), Hôpital Raymond Poincaré [AP-HP], Service de cardiologie pédiatrique [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), Institut de cardiologie [CHU Pitié-Salpêtrière], CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)
Subjects: Male, cardiomyopathies, 0301 basic medicine, Genotype-phenotype correlation, Genotype, Filamins, Cardiomyopathy, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, Sudden cardiac death, Electrocardiography, 03 medical and health sciences, Prevalence, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Genetic Testing, FLNC, Indel, Alleles, Genetic Association Studies, Genetics (clinical), next generation sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Genetic Variation, High-Throughput Nucleotide Sequencing, Dilated cardiomyopathy, Sequence Analysis, DNA, medicine.disease, Magnetic Resonance Imaging, Phenotype, Pedigree, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Echocardiography, Mutation, Female, business, myopathy
Abstract: International audience; Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.
Published: 2019
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2. Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort

Author: Gérald Le Gac, Alexandra Martins, Pascaline Gaildrat, Florence Coulet, Françoise Revillon, Antoine Rousselin, Sandrine M. Caputo, Marine Guillaud-Bataille, Chandran Ka, Mélanie Léoné, Nadia Boutry-Kryza, Virginie Caux-Moncoutier, Claude Férec, Capucine Delnatte, Danielle Muller, Grégoire Davy, Amanda B. Spurdle, Maria Rossing, Raphaël Leman, Yann Fichou, Michael T. Parsons, Barbara Wappenschmidt, Violaine Bourdon, Joanna Sokolowska, Nicolas Sevenet, Claude Houdayer, M.-P. Audrézet, Brigitte Bressac-de Paillerets, Françoise Bonnet-Dorion, Sylvie Mazoyer, Gaia Castelain, Sophie Krieger, Laurent Castera, Etienne Rouleau, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Institut Curie [Paris], Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), 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), 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), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University Hospital of Cologne [Cologne], IT University of Copenhagen (ITU), Centre Paul Strauss, CRLCC Paul Strauss, Laboratoire d'oncogénétique moléculaire, Unite d'Oncogenese Virale, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, QIMR Berghofer Medical Research Institute, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique médicale [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), Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang Bretagne, EFS, Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), COMBE, Isabelle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, 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), IT University of Copenhagen, Institut Gustave Roussy (IGR), Service d'Oncologie Génétique, de Prévention et Dépistage, Laboratoire d'Oncologie Moléculaire Humaine, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, CHU Pontchaillou [Rennes], Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre René Gauducheau, and CRLCC René Gauducheau
Subjects: 0301 basic medicine, International Cooperation, RNA Splicing, In silico, Spice, Breast Neoplasms, Computational biology, Biology, Sensitivity and Specificity, Set (abstract data type), 03 medical and health sciences, Exon, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Consensus sequence, RNA and RNA-protein complexes, Humans, Computer Simulation, 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, Internet, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], BRCA1 Protein, Intron, Computational Biology, Genetic Variation, Reproducibility of Results, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], In vitro, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA splicing, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, RNA Splice Sites, RNA characterisation and manipulation, Corrigendum, Computational Methods, Optimal decision
Abstract: Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5′ and 3′ consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions from SpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).
Published: 2018
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3. A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

Author: Guéant, Jean-Louis, Chéry, Céline, Oussalah, Abderrahim, Nadaf, Javad, Coelho, David, Josse, Thomas, Flayac, Justine, Robert, Aurélie, Koscinski, Isabelle, Gastin, Isabelle, Filhine-Tresarrieu, Pierre, Pupavac, Mihaela, Brebner, Alison, Watkins, David, Pastinen, Tomi, Montpetit, Alexandre, Hariri, Fadi, Tregouët, David, Raby, Benjamin A, Chung, Wendy K., Morange, Pierre-Emmanuel, Froese, D. Sean, Baumgartner, Matthias R., Benoist, Jean-François, Ficicioglu, Can, Marchand, Virginie, Motorin, Yuri, Bonnemains, Chrystèle, Feillet, François, Majewski, Jacek, Rosenblatt, David S., GONNET, JULIE, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), McGill University = Université McGill [Montréal, Canada], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-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), Harvard Medical School [Boston] (HMS), University of Missouri [Columbia] (Mizzou), University of Missouri System, 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), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), University hospital of Zurich [Zurich], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia (CHOP ), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), McGill University, Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), 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], University of Missouri [Columbia], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition (C2VN), University of Pennsylvania [Philadelphia], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: MESH: Mutation, MESH: Metabolism, Inborn Errors, MESH: Pedigree, Science, MESH: Azacitidine, MESH: Peroxiredoxins, MESH: Carrier Proteins, MESH: Base Sequence, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Epistasis, Genetic, lcsh:Science, MESH: Heterozygote, MESH: Humans, MESH: Alleles, nutritional and metabolic diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Male, MESH: Vitamin B 12, MESH: Enzyme Inhibitors, MESH: Fibroblasts, MESH: Family Health, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:Q, MESH: Whole Genome Sequencing, MESH: Female
Abstract: To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name “epi-cblC”. The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios., Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.
Published: 2018
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4. Impact of coronary artery disease in patients undergoing transcatheter aortic valve replacement: Insights from the FRANCE-2 registry

Author: Alain Leguerrier, Didier Carrié, Patrick Donzeau-Gouge, Thierry Lefèvre, Stephan Chassaing, Etienne Puymirat, Jean Fajadet, Martine Gillard, Emmanuel Teiger, Pascal Leprince, Hervé Le Breton, Michel Lievre, Eric Durand, Jean-Philippe Collet, Dominique Himbert, Didier Tchetche, Karine Chevreul, Bernard Lung, Hélène Eltchaninoff, Romain Didier, Florence Leclercq, Didier Blanchard, Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Département Cardiologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de cardiologie [CHU Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique Pasteur, Clinique Pasteur [Toulouse], 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), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Clinique Saint Gatien, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cardiovasculaire Paris Sud (ICPS), Optimisation des régulations physiologiques (ORPHY (EA 4324)), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Edwards Lifesciences, Medtronic, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [APHP], Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)
Subjects: Male, [SDV]Life Sciences [q-bio], medicine.medical_treatment, CAD, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary Angiography, Severity of Illness Index, Coronary artery disease, 0302 clinical medicine, Valve replacement, Risk Factors, Registries, 030212 general & internal medicine, Coronary Artery Bypass, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, education.field_of_study, Incidence, Hazard ratio, General Medicine, 3. Good health, Survival Rate, Treatment Outcome, medicine.anatomical_structure, Aortic Valve, Cardiology, Female, France, Cardiology and Cardiovascular Medicine, Artery, medicine.medical_specialty, Transcatheter aortic, Population, Clinical Investigations, Revascularization, Risk Assessment, Transcatheter Aortic Valve Replacement, 03 medical and health sciences, Percutaneous Coronary Intervention, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, In patient, cardiovascular diseases, education, business.industry, Percutaneous coronary intervention, Aortic Valve Stenosis, medicine.disease, Confidence interval, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: BACKGROUND: Coronary artery disease (CAD) is common in patients undergoing transcatheter aortic valve replacement (TAVR). However, the impact of CAD distribution before TAVR on short‐ and long‐term prognosis remains unclear. HYPOTHESIS: We hypothesized that the long‐term clinical impact differs according to CAD distribution in patients undergoing TAVR using the FRench Aortic National CoreValve and Edwards (FRANCE‐2) registry. METHODS: FRANCE‐2 is a national French registry including all consecutive TAVR performed between 2010 and 2012 in 34 centers. Three‐year mortality was assessed in relation to CAD status. CAD was defined as at least 1 coronary stenosis >50%. RESULTS: A total of 4201 patients were enrolled in the registry. For the present analysis, we excluded patients with a history of coronary artery bypass. CAD was reported in 1252 patients (30%). Half of the patients presented with coronary multivessel disease. CAD extent was associated with an increase in cardiovascular risk profile and in logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (from 19.3% ± 12.8% to 21.9% ± 13.5%, P < 0.001). Mortality at 30 days and 3 years was 9% and 44%, respectively, in the overall population. In multivariate analyses, neither the presence nor the extent of CAD was associated with mortality at 3 years (presence of CAD, hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78‐1.07). A significant lesion of the left anterior descending (LAD) was associated with higher 3‐year mortality (HR: 1.42; 95% CI: 1.10‐1.87). CONCLUSIONS: CAD is not associated with decreased short‐ and long‐term survival in patients undergoing TAVR. The potential deleterious effect of LAD disease on long‐term survival and the need for revascularization before or at the time of TAVR should be validated in a randomized control trial.
Published: 2017
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5. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Author: Girard, Elodie, Eon-Marchais, Séverine, Olaso, François, Renault, Anne, Damiola, Francesca, Dondon, Marie-Gabrielle, Barjhoux, Laure, Goidin, Didier, Meyer, François, Le Gal, Dorothée, Beauvallet, Juana, Mebirouk, Noura, Lonjou, Christine, Coignard, Julie, Marcou, Morgane, Cavaciuti, Eve, Baulard, François, Bihoreau, François, Cohen-Haguenauer, Odile, Leroux, Dominique, Penet, Jean, Fert-Ferrer, Sandra, Colas, Chrystelle, Frebourg, Thierry, Eisinger, François, Adenis, Claude, Fajac, Anne, Gladieff, Laurence, Tinat, Julie, Floquet, Anne, Chiesa, Jean, Giraud, Sophie, Mortemousque, Isabelle, Soubrier, Florent, Audebert-Bellanger, Séverine, Limacher, Jean-Marc, Lasset, Christine, Lejeune-Dumoulin, Sophie, Dreyfus, Catherine, Bignon, Yves-Jean, Longy, Michel, Pujol, Pascal, Venat-Bouvet, Laurence, Bonadona, Valérie, Berthet, Pascaline, Luporsi, Elisabeth, Maugard, Christine, Noguès, Catherine, Delnatte, Capucine, Fricker, Paul, Gesta, Paul, Faivre, Laurence, Lortholary, Alain, Buecher, Bruno, Caron, Olivier, Gauthier-Villars, Marion, Coupier, Isabelle, Servant, Nicolas, Boland, Anne, Mazoyer, Sylvie, Deleuze, Jean-François, Stoppa-Lyonnet, Dominique, Andrieu, Nadine, Lesueur, Fabienne, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-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), 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), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Life Sciences and Diagnostics Group [Les Ulis, France], Agilent Technologies France, Laboratoire Information, Milieux, Médias, Médiations - EA 3820 (I3M), 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)-Université de Toulon (UTLN), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Traitement Algorithmique et Matériel de la Communication, de l'Information et de la Connaissance (TAMCIC), Ecole Nationale Supérieure des Télécommunications de Bretagne-Centre National de la Recherche Scientifique (CNRS), CRLCC Jean Godinot, Centre Hospitalier de Chambéry (C.H.de Chambéry), 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), Département de Génétique [Institut Curie, Paris] (Unité de Pharmacogénomique), Institut Curie [Paris], 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), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Claudius Regaud, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département d'oncologie médicale, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital pasteur [Colmar], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Sainte Catherine [Avignon], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Département de pathologie, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Hôpital Dupuytren [CHU Limoges], Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Consultation d'Oncogénétique, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Alexis Vautrin (CAV), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Laboratoire d'Oncogénétique, CRLCC René Huguenin, CRLCC René Gauducheau, Service d'Oncologie Médicale [Strasbourg] (UNICANCER Centre Paul Strauss), Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Catherine-de-Sienne [Nantes] (CCS), Service de Génétique Oncologique, Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Unité d'Oncogénétique, CRLCC Val d'Aurelle - Paul Lamarque, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Grant sponsor: comprehensive cancer center SiRIC, Grant numbers: INCa-DGOS-4654, Grant sponsor: Fondation ARC pour la recherche sur le cancer, Grant numbers: PJA 20151203365, Grant sponsor: France Génomique National infrastructure, Grant numbers: ANR-10-INBS-09, Grant sponsor: Institut National du Cancer (INCa), Grant numbers: b2008-029/LL-LC, Grant sponsor: Ligue Comité de Paris, Grant numbers: RS15/75-78, Grant sponsor: Ligue Nationale Contre le Cancer, Grant numbers: PRE05/DSL PRE07/DSL PRE11/NA., Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), 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), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des cancers : Radiocarcinogénèse et effets iatrogènes des traitements, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), E06, Centre de Recherche en Cancérologie de Lyon (CRCL), 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)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), 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 Pierre et Marie Curie - Paris 6 (UPMC), CRESS, Université de Franche-Comté (UFC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, CHU Saint-Antoine [APHP], Génétique du cancer et des maladies neuropsychiatriques (GMFC), Centre oscar lambert, service d'hématologie chu, CHU Tenon [APHP], CRLCC Institut Claudius Regaud, Centre Beninois pour l'Environnement et le développement économique et Social (CEBEDES), Service de Génétique Clinique [CHRU Nïmes], Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), 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], Service de Pédiatrie et de Génétique Médicale, Hôpital Jeanne de Flandre [Lille], Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Université Clermont Auvergne (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin, CRLCC Jean Perrin, Institut Bergonié - CRLCC Bordeaux, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, 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) (APHP)-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) (APHP)-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 Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de diagnostic génétique, Hôpital Universitaire de Strasbourg, Strasbourg, Centre René Gauducheau, Genetic and Immunology Medical Institute (GIMI), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Fédération Francophone de la Cancérologie Digestive, FFCD, Institut Gustave Roussy (IGR), Service d'oncogénétique, Institut Curie, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Equipe 6, Université Paris Descartes - Paris 5 (UPD5), Méthodologie statistique et épidémiologie génétique des maladies multifactorielles, Institut National de la Santé et de la Recherche Médicale (INSERM), Section Génétique - Groupe Prédispositions génétiques au cancer, Centre International de Recherche contre le Cancer (CIRC), MINES ParisTech - École nationale supérieure des mines de Paris, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure des Télécommunications de Bretagne, 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), Université Lille Nord de France (COMUE)-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Andrieu, Nadine, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Adult, DNA Repair, case-control study, [SDV]Life Sciences [q-bio], Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Risk Assessment, Cancer Genetics and Epigenetics, breast cancer, multigene panel testing, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, Genetic Predisposition to Disease, Genetic Testing, Aged, Aged, 80 and over, [SDV.GEN]Life Sciences [q-bio]/Genetics, Siblings, case–control study, Middle Aged, [SDV] Life Sciences [q-bio], variant, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, exome sequencing
Abstract: Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF = 17.4 vs. ORMV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates., What's new? Pathogenic variants in BRCA1 and BRCA2 only explain the genetic cause of about 10% of hereditary breast and ovarian cancer families, and the clinical usefulness of testing other genes following the recent introduction of cost‐effective multigene panel sequencing in diagnostics laboratories remains questionable. This large case‐control study describes genetic variation in 113 DNA repair genes and specifies breast cancer relative risks associated with rare deleterious‐predicted variants in PALB2, ATM, and CHEK2. Importantly, different types of variants within the same gene can lead to different risk estimates. The results may help improve risk prediction models and define gene‐specific consensus management guidelines.
Published: 2019
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6. The Genetic Landscape of Renal Complications in Type 1 Diabetes

Author: Daniel Ziemek, Stephen S. Rich, Linda T Hiraki, Maija Parkkonen, Mary Julia Brosnan, Claes Ladenvall, Alexander P. Maxwell, Claudio Cobelli, Niina Sandholm, Helen M. Colhoun, Marco Manfrini, Harshal Deshmukh, Daniel Gordin, David B. Dunger, Valeriya Lyssenko, Thorhildur Juliusdottir, Andrew D. Paterson, Natalie R. van Zuydam, Samy Hadjadj, João Fadista, Paul M. McKeigue, Rany M. Salem, Nikolay Oskolkov, Emma H. Dahlström, M. Loredana Marcovecchio, Jaakko Tuomilehto, Erkka Valo, Jason D. Cooper, Jose C. Florez, Mark I. McCarthy, Joel N. Hirschhorn, Marcus G. Pezzolesi, Maria Lajer, Leif Groop, Valma Harjutsalo, Alberto Malovini, Andrzej S. Krolewski, Riccardo Bellazzi, Francesco Sambo, Carol Forsblom, David-Alexandre Trégouët, Amy Jayne McKnight, Emma Ahlqvist, Barbara Di Camillo, N. William Rayner, Peter Rossing, Per-Henrik Groop, Eric B. Fauman, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Public Health [Belfast, Northern Ireland, UK], Queen's University [Belfast] (QUB), University of Edinburgh, Laboratory for BioMedical Informatics (BMI), University of Pavia, Steno Diabetes Center of Copenhagen [Gentofte, Denmark], CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Department of Clinical Sciences, Lund University [Lund]-Lund University Diabetes Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], Università degli Studi di Pavia = University of Pavia (UNIPV), Lund University [Lund], and University of Oxford
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Glucuronate, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, Genome-wide association study, Disease, Type 2 diabetes, Biology, genetics and development, Kidney, Bioinformatics, whole exome sequencing, Young Adult, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Up Front Matters, Internal medicine, Diabetes mellitus, medicine, Genetic predisposition, Humans, Diabetic Nephropathies, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Type 1 diabetes, genome-wide association study, General Medicine, Middle Aged, ta3121, medicine.disease, diabetic kidney disease, Dreams, 3. Good health, Basic Research, Diabetes Mellitus, Type 1, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Nephrology, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease
Abstract: Diabetes is the leading cause of end stage renal disease. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2,843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (p=6x10-3 7 ). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (p=2.2×10-5) and the risk of type 2 diabetes (p=6.1x10-4 11 ) were associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (p=1.1×10-4 13 ). Pathway analysis implicated ascorbate and aldarate metabolism (p=9×10-6), and pentose and glucuronate interconversions (p=3×10-6 14 ) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
Published: 2017
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7. Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study

Author: Erin N. Smith, Immaculata DeVivo, Paul M. Ridker, Marta Crous-Bou, Weihong Tang, Marine Germain, Hugoline G. de Haan, Jennifer A. Brody, Sara Lindström, Christopher Kabrhel, Francine Grodstein, Nicholas L. Smith, Mariza de Andrade, Astrid van Hylckama Vlieg, Daniel I. Chasman, Pierre-Emmanuel Morange, John A. Heit, David-Alexandre Trégouët, ALESSI, Marie-Christine, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, 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), The Scripps Translational Science Institute and Scripps Health, Fibrinolyse et Pathologie Vasculaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Department of Thrombosis and Hemostasis (LEIDEN - DTH), Leiden University Medical Center (LUMC), Department of Thrombosis and Haemostasis, Brigham and Women's Hospital [Boston], Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Department of Epidemiology, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Massachusetts General Hospital [Boston], Program in Genetic Epidemiology and Statistical Genetics ( PGESG - BOSTON ), 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], 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 ), Department of Thrombosis and Hemostasis ( LEIDEN - DTH ), Department of Health Sciences Research [Mayo Clinic] ( HSR ), Massachusetts General Hospital [Boston] ( MGH ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota [Twin Cities], and Universiteit Leiden-Universiteit Leiden
Subjects: Male, Genome-wide association study, 030204 cardiovascular system & hematology, Body Mass Index, 0302 clinical medicine, 030212 general & internal medicine, Genetics (clinical), 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Incidence, Confounding, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Female, Adult, medicine.medical_specialty, venous thromboembolism, SNP, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, cardiovascular diseases, Obesity, Proportional Hazards Models, association, nutritional and metabolic diseases, Mendelian Randomization Analysis, medicine.disease, equipment and supplies, Logistic Models, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Observational study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Body mass index, Genome-Wide Association Study
Abstract: International audience; Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02–1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30–1.93 per standard deviation increase in BMI, P = 5.8 × 10−6). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.
Published: 2017
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8. Platelet protease nexin-1, a serpin that strongly influences fibrinolysis and thrombolysis.: Platelet Protease Nexin-1 Is Antithrombolytic

Author: Yacine Boulaftali, Marie-Christine Bouton, Martine Jandrot-Perrus, Jean-Philippe Collet, Benoît Ho-Tin-Noé, Stéphane Loyau, Véronique Arocas, Laurence Venisse, Déborah François, Benjamin Richard, Ana Pena, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Inserm, Université Paris 7, and Fondation de France (grant 2009002497). Y.B. was supported by the Fondation pour la Recherche Médicale (FRM)., and Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée
Subjects: Blood Platelets, Male, thrombolysis, Plasmin, medicine.medical_treatment, 030204 cardiovascular system & hematology, Serpin, Cytoplasmic Granules, Tissue plasminogen activator, Antibodies, Article, Fibrin, Mice, 03 medical and health sciences, 0302 clinical medicine, Thrombin, Physiology (medical), Serpin E2, Fibrinolysis, medicine, Animals, Humans, Thrombolytic Therapy, Platelet, Fibrinolysin, serpinE2, Blood Coagulation, 030304 developmental biology, 0303 health sciences, biology, business.industry, Plasminogen, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Thrombolysis, Molecular biology, Mice, Mutant Strains, 3. Good health, Mice, Inbred C57BL, Tissue Plasminogen Activator, platelets, biology.protein, Female, fibrinolysis, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract: Background— Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma, but we have shown recently that PN-1 is present within the α-granules of platelets. Methods and Results— In this study, the role of platelet PN-1 in fibrinolysis was investigated with the use of human platelets incubated with a blocking antibody and platelets from PN-1–deficient mice. We showed by using fibrin-agar zymography and fibrin matrix that platelet PN-1 inhibited both the generation of plasmin by fibrin-bound tissue plasminogen activator and the activity of fibrin-bound plasmin itself. Rotational thromboelastometry and laser scanning confocal microscopy were used to demonstrate that PN-1 blockade or deficiency resulted in increased clot lysis and in an acceleration of the lysis front. Protease nexin-1 is thus a major determinant of the lysis resistance of platelet-rich clots. Moreover, in an original murine model in which thrombolysis induced by tissue plasminogen activator can be measured directly in situ, we observed that vascular recanalization was significantly increased in PN-1–deficient mice. Surprisingly, general physical health, after tissue plasminogen activator–induced thrombolysis, was much better in PN-1–deficient than in wild-type mice. Conclusions— Our results reveal that platelet PN-1 can be considered as a new important regulator of thrombolysis in vivo. Inhibition of PN-1 is thus predicted to promote endogenous and exogenous tissue plasminogen activator–mediated fibrinolysis and may enhance the therapeutic efficacy of thrombolytic agents.
Published: 2011
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9. Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling

Author: Kristell Wanherdrick, Sonia-Athina Karabina, Gérard Lambeau, Rajai Atout, Ewa Ninio, Seraya Maouche, François Cambien, Sarah Gora, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (... - 2019) (UNS)
Subjects: Umbilical Veins, Cytoskeleton organization, p38 mitogen-activated protein kinases, Blotting, Western, Eukaryotic Initiation Factor-2, Fluorescent Antibody Technique, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Serine-Threonine Kinases, 030204 cardiovascular system & hematology, Biology, Endoplasmic Reticulum, Biochemistry, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Endoribonucleases, Genetics, medicine, Humans, Gene Silencing, Phospholipases A2, Secretory, Molecular Biology, Cells, Cultured, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, 0303 health sciences, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, ATF6, Endoplasmic reticulum, Interleukin-8, Endothelial Cells, Activating Transcription Factor 6, 3. Good health, Cell biology, Lipoproteins, LDL, Endothelial stem cell, Unfolded Protein Response, Unfolded protein response, medicine.symptom, Signal Transduction, Biotechnology
Abstract: International audience; Secreted phospholipases A2 (sPLA2s) are present in atherosclerotic plaques and are now considered novel attractive therapeutic targets and potential biomarkers as they contribute to the development of atherosclerosis through lipoprotein-dependent and independent mechanisms. We have previously shown that hGX-sPLA2-phospholipolyzed LDL (LDL-X) induces proinflammatory responses in human umbilical endothelial cells (HUVECs); here we explore the molecular mechanisms involved. Global transcriptional gene expression profiling of the response of endothelial cells exposed to either LDL or LDL-X revealed that LDL-X activates multiple distinct cellular pathways including the unfolded protein response (UPR). Mechanistic insight showed that LDL-X activates UPR through calcium depletion of intracellular stores, which in turn disturbs cytoskeleton organization. Treatment of HUVECs and aortic endothelial cells (HAECs) with LDL-X led to activation of all 3 proximal initiators of UPR: eIF-2alpha, IRE1alpha, and ATF6. In parallel, we observed a sustained phosphorylation of the p38 pathway resulting in the phosphorylation of AP-1 downstream targets. This was accompanied by significant production of the proinflammatory cytokines IL-6 and IL-8. Our study demonstrates that phospholipolyzed LDL uses a range of molecular pathways including UPR to initiate endothelial cell perturbation and thus provides an LDL oxidation-independent mechanism for the initiation of vascular inflammation in atherosclerosis.-Gora, S., Maouche, S., Atout, R., Wanherdrick, K., Lambeau, G., Cambien, F., Ninio, E., Karabina, S.-A. Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling.
Published: 2010
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10. Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft

Author: Agnès Nelva, Christine Francannet, Sylvaine Cordier, Elisabeth Robert-Gnansia, Claire Perret, Christine Herman, Marie-Paule Vazquez, David M. Iovannisci, Michel Bahuau, Cécile Chevrier, Edward J. Lammer, Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes (UR)-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), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Children's Hospital Oakland Research, Registre des Malformations Rhône-Alpes, REMERA, Centre d'Etude des Malformations Congénitales (CEMC), Centre d'Etude des Malformations Congénitales, Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Children's Hospital Oakland Research Institute, hildren's Hospital Oakland Research Institute, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], 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 stomatologie et chirurgie maxillo-faciale [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), and Forgeron, Christine
Subjects: Male, Passive smoking, Physiology, MESH: Logistic Models, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Tobacco smoke, MESH: Genotype, MESH: Pregnancy, Pregnancy, Risk Factors, MESH: Risk Factors, Smoke, Medicine, MESH: Maternal Exposure, MESH: Tobacco, Genetics (clinical), Glutathione Transferase, Genetics, 0303 health sciences, education.field_of_study, Smoking, 030305 genetics & heredity, MESH: Genetic Predisposition to Disease, MESH: Smoke, MESH: Case-Control Studies, MESH: Infant, 3. Good health, Cleft Palate, Maternal Exposure, Female, France, MESH: Pregnancy Trimester, First, MESH: Smoking, Genotype, Cleft Lip, Population, Genetic determinism, 03 medical and health sciences, Tobacco, MESH: Polymorphism, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Risk factor, education, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, MESH: Glutathione Transferase, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, business.industry, MESH: Cleft Lip, Infant, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, medicine.disease, MESH: Male, MESH: France, Pregnancy Trimester, First, Logistic Models, MESH: Cleft Palate, Case-Control Studies, Relative risk, business, MESH: Female
Abstract: International audience; Maternal tobacco consumption is considered as a risk factor for nonsyndromic oral clefts. However, this risk is moderate and may be modulated by genetic susceptibilities, including variants of the TGFA, TGFB3 and MSX1 developmental genes and polymorphisms of genes of the CYP (1A1, 2E1) and GST (M1, T1) families involved in metabolic pathways of tobacco smoke compounds. This French case-control study (1998-2001; 240 nonsyndromic cases, 236 controls) included a case-parent design (175 triad-families) that made it possible to distinguish the direct effect of the child's genotype and maternally mediated effects. Maternal smoking during the first trimester of pregnancy was not associated with the oral cleft risk in this population, but we observed statistically significant increased risks associated with maternal exposure to environmental tobacco smoke (ETS). No variant of any of the three developmental genes was significantly associated with oral cleft. The fetal CYP1A1*2C variant allele was associated with a statistically significant decreased risk, compared with the homozygous wild-type: relative risk = 0.48, 95% confidence interval: 0.2, 1.0. Suggestive reduced risks were also observed for the maternal CYP1A1*2C allele and the fetal CYP2E1*5 allele. The GSTM1 and GSTT1 deletions appeared to play no role. Our findings suggest some interactions, with the strongest between ETS and CYP1A1 or MSX1 and between maternal smoking and CYP2E1. We did not confirm the maternal smoking-infant GSTT1 null interaction previously reported by other investigators.
Published: 2008
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11. Pharmacogenomics and antihypertensive drugs: a path toward personalized medicine

Author: Nicolas Gambier, Jean-Brice Marteau, Sophie Visvikis-Siest, Elise Jeannesson, Gérard Siest, Centre du Médicament [Nancy], Université Henri Poincaré - Nancy 1 (UHP), Service de Pharmacologie Clinique et Toxicologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), and Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV)
Subjects: Pharmacology, Drug, 0303 health sciences, Candidate gene, business.industry, [SDV]Life Sciences [q-bio], media_common.quotation_subject, General Medicine, Disease, 030204 cardiovascular system & hematology, Bioinformatics, 3. Good health, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Pharmacogenomics, Proteome, Molecular Medicine, Medicine, Personalized medicine, business, ComputingMilieux_MISCELLANEOUS, Pharmacogenetics, 030304 developmental biology, media_common
Abstract: Pharmacogenomics focuses on genes and the transcriptome and proteome. It has the potential to enhance healthcare management by improving disease diagnosis and implementing treatments adapted to each patient. Previously, pharmacogenetics of candidate genes focused on clinical research. It is now extended by using genome-wide approaches to elucidate the inherited basis of differences between individuals in their response to drugs. We summarize relevant polymorphisms of genes involved in the pharmacokinetics and pharmacodynamics of antihypertensive drugs and we give an overview of the state of pharmacogenomic research in hypertension medicine. Even if things are getting better, current pharmacogenetic studies still lack power, adequate selection of candidate genes and knowledge of their functions at the physiological level. Finally, some specific end point phenotypes (i.e., peptides or proteins related to the metabolic cycle targeted by the drug) should be integrated to propose data that are easily applicable to personalized medicine.
Published: 2007
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12. Fetal and maternalMTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts

Author: Sylvaine Cordier, Huiping Zhu, Elisabeth Robert-Gnansia, Christine Francannet, Agnès Nelva, Michel Bahuau, Richard H. Finnell, Cécile Chevrier, Claire Perret, Christine Herman, Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], 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), Registre des Malformations Rhône-Alpes, REMERA, Centre d'Etude des Malformations Congénitales (CEMC), Centre d'Etude des Malformations Congénitales, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: cleft lip, MESH: Genotype, MESH: Pregnancy, Pregnancy, Polymorphism (computer science), Genotype, Medicine, Genetics (clinical), cleft palate, 0303 health sciences, biology, 030305 genetics & heredity, vitamin, MESH: Genetic Predisposition to Disease, MESH: Methylenetetrahydrofolate Reductase (NADPH2), MESH: Case-Control Studies, 3. Good health, MESH: Maternal Nutritional Physiological Phenomena, nutrition, Female, medicine.medical_specialty, MESH: Mutation, Offspring, folate, MESH: Folic Acid, folic acid, 03 medical and health sciences, MESH: Diet, Internal medicine, MESH: Polymorphism, Genetic, Genetics, Humans, Genetic Predisposition to Disease, Risk factor, Methylenetetrahydrofolate Reductase (NADPH2), 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, business.industry, MESH: Cleft Lip, Case-control study, Maternal Nutritional Physiological Phenomena, Odds ratio, medicine.disease, methylenetetrahydrofolate reductase, Diet, Endocrinology, MESH: Cleft Palate, Case-Control Studies, Methylenetetrahydrofolate reductase, Mutation, biology.protein, business, MESH: Female
Abstract: International audience; The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts.
Published: 2007
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13. Identification of Hypoxia-response Element in the Human Endothelial Nitric-oxide Synthase Gene Promoter

Author: Sophie Nadaud, Florent Soubrier, Monique Agrapart, Florence Coulet, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Nitric Oxide Synthase Type III, Transcription, Genetic, [SDV]Life Sciences [q-bio], Deferoxamine, Biology, Response Elements, Biochemistry, Transcription (biology), Basic Helix-Loop-Helix Transcription Factors, Humans, Luciferase, Hypoxia, Promoter Regions, Genetic, Molecular Biology, Gene, Transcription factor, Cells, Cultured, Messenger RNA, Expression vector, Base Sequence, Nuclear Proteins, Promoter, Cell Biology, Hypoxia-Inducible Factor 1, alpha Subunit, Molecular biology, DNA-Binding Proteins, Enzyme Induction, Mutation, Mutagenesis, Site-Directed, Trans-Activators, Endothelium, Vascular, Hypoxia-Inducible Factor 1, Nitric Oxide Synthase, Transcription Factors
Abstract: The human endothelial nitric-oxide synthase gene (heNOS) is constitutively expressed in endothelial cells, and its expression is induced under hypoxia. The goal of this study was to search for regulatory elements of the endothelial nitric-oxide synthase (eNOS) gene responsive to hypoxia. Levels of eNOS mRNA, measured by real time reverse transcriptase-PCR analysis, were increased, and heNOS promoter activity was enhanced by hypoxia as compared with normoxia control experiments. Promoter truncation followed by footprint analysis allowed the mapping and identification of the hypoxia-responsive elements at position -5375 to -5366, closely related to hypoxia-inducible factor (HIF)-responsive element (HRE). To test whether known HIF-1 and HIF-2 are involved in hypoxia-induced heNOS promoter activation, HMEC-1 and HUVEC were transiently transfected with HIF-1alpha and HIF-1beta or HIF-2alpha and HIF-1beta expression vectors. Exogenous HIF-2 markedly increased luciferase reporter activity driven by the heNOS promoter in its native location. The induction of luciferase was conserved with the antisense construct and was increased in cotransfection experiments when this fragment was cloned 5' to the proximal 785-bp fragment of the eNOS promoter. Deletion analysis and site-directed mutagenesis demonstrated that the two contiguous HIF consensus binding sites spanning bp -5375 to -5366 relative to the transcription start site were both functional for heNOS promoter activity induction by hypoxia and by HIF-2 overexpression. In conclusion, we demonstrate that heNOS is a hypoxia-inducible gene, whose transcription is stimulated through HIF-2 interaction with two contiguous HRE sites located at -5375 to -5366 of the heNOS promoter.
Published: 2003
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14. Acetylation of TAFI68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription

Author: Sophie Nadaud, Viola Muth, Renate Voit, Ingrid Grummt, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Saccharomyces cerevisiae Proteins, Transcription, Genetic, [SDV]Life Sciences [q-bio], Response element, Hydroxamic Acids, DNA, Ribosomal, Gene Expression Regulation, Enzymologic, Histone Deacetylases, Article, General Biochemistry, Genetics and Molecular Biology, Mice, Sirtuin 2, Sp3 transcription factor, Acetyltransferases, RNA Polymerase I, Animals, Sirtuins, Gene Silencing, Molecular Biology, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Histone Acetyltransferases, Terminator Regions, Genetic, General Immunology and Microbiology, biology, General transcription factor, General Neuroscience, TATA-Box Binding Protein, Acetylation, Promoter, Histone acetyltransferase, Molecular biology, Recombinant Proteins, DNA-Binding Proteins, Protein Subunits, TAF2, Trans-Activators, biology.protein, Transcription factor II D, Pol1 Transcription Initiation Complex Proteins, Protein Binding, Transcription Factors
Abstract: International audience; Mammalian rRNA genes are preceded by a terminator element that is recognized by the transcription termination factor TTF-I. In exploring the functional significance of the promoter-proximal terminator, we found that TTF-I associates with the p300/CBP-associated factor PCAF, suggesting that TTF-I may target histone acetyltransferase to the rDNA promoter. We demonstrate that PCAF acetylates TAF(I)68, the second largest subunit of the TATA box-binding protein (TBP)-containing factor TIF-IB/SL1, and acetylation enhances binding of TAF(I)68 to the rDNA promoter. Moreover, PCAF stimulates RNA polymerase I (Pol I) transcription in a reconstituted in vitro system. Consistent with acetylation of TIF-IB/SL1 being required for rDNA transcription, the NAD(+)-dependent histone deacetylase mSir2a deacetylates TAF(I)68 and represses Pol I transcription. The results demonstrate that acetylation of the basal Pol I transcription machinery has functional consequences and suggest that reversible acetylation of TIF-IB/SL1 may be an effective means to regulate rDNA transcription in response to external signals.
Published: 2001
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15. In Vitro fertilization failure of normozoospermic men: search for a lack of testicular isozyme of angiotensin-converting enzyme

Author: Jean-Marie Antoine, Isabelle Berthaut, Vanina De Larouziere, Selima Fourati Ben Mustapha, Mélanie Eyries, Jacqueline Mandelbaum, Célia Ravel, Florence Coulet, Florent Soubrier, BMC, Ed., Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-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), Clinique de Promotion des Sciences de la Reproduction - Les Jasmins (CPSR), Clinique de Promotion des Sciences de la Reproduction, Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR14 - Université Pierre et Marie Curie - Paris 6 (UPMC), Histologie et biologie de la reproduction, Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: medicine.medical_specialty, endocrine system, Infertilité masculine, Urology, Sperm-oocyte interaction, Semen, Biology, IVF failure, Interaction spermatozoïde-ovocyte, Isozyme, Male infertility, Andrology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Enzyme de conversion de l′angiotensine, Renin–angiotensin system, medicine, Zone pellucide, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Spermatozoïde, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Zona pellucida, reproductive and urinary physiology, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, urogenital system, Angiotensin-converting enzyme, medicine.disease, Sperm, Angiotensin II, Spermatozoa, Echec de FIV, medicine.anatomical_structure, Endocrinology, Reproductive Medicine, biology.protein, Angiotensin converting enzyme, Research Article
Abstract: Angiotensin converting enzyme (ACE) is a metalloprotease with two isoforms. The somatic isoform is a key component of the renin-angiotensin system; its main function is to hydrolyse angiotensin I into angiotensin II. The germinal or testicular isoform (tACE) located at the plasma membrane of the spermatozoa, plays a crucial role in the spermatozoa-oocyte interaction during in vivo fertilization, in rodents. Disruption of the tACE in mice has revealed that homozygous male tACE-/- sire few pups despite mating normally. Few spermatozoa from these tACE-/- mice are bound to the zona pellucida (ZP) despite normal semen parameters. Based on these findings in mice models, we hypothesized that some infertile men that have the same phenotype as the tACE-/- mice, ie normal semen parameters and a lack of sperm bind to the ZP in vitro, may have a tACE defect.Twenty four men participated to this study. The case subjects (n = 10) had normal semen parameters according to the WHO guidelines (WHO 1999) but a total in vitro fertilization failure with absence of sperm fixation to the ZP. The control subjects (n = 14) also had normal semen parameters and a normal fertilization rate ≥65%. We investigated the tACE expression in spermatozoa by Western-Blot and performed a DNA sequencing of the tACE gene.Three case-subjects and one control-subject had no tACE expression. There were no statistic differences between the two groups. No mutation was detected in the tACE DNA sequence.Our results didn't show any involvement of tACE in human fertilization especially in ZP binding.L’enzyme de conversion de l′angiotensine (ACE) est une métalloprotéase qui se présente sous deux isoformes. Une isoforme somatique qui intervient dans la régulation de la pression artérielle via le système rénine-angiotensine et une isoforme testiculaire spermatique (ACEt) qui interviendrait dans la fixation du spermatozoïde aux enveloppes ovocytaires (zone pellucide et/ou oelemme). Des expériences d’invalidation du gène de l′ACEt chez la souris ont montré que les mâles homozygotes ACEt−/− présentaient une faible descendanceVingt quatre patients ont été inclus dont 10 cas avec un sperme normal et un échec total de fécondation lors d’une FIV et 14 témoins ayant les mêmes caractéristiques spermatiques mais présentant de bons taux de fécondation (≥65%). L’étude de l’expression protéique de l’ACEt a été faite par western-blot sur les culots de spermatozoïdes. Un séquençage du gène codant pour l′ACEt a été fait sur l′ADN lymphocytaire.Trois cas et un témoin présentaient un défaut d’expression de l′ACEt sans diffèrence statistiquement significative entre ces deux groupes. En PCR, aucune mutation n’a été retrouvée après séquençage du gène de l′ACEt.Nos résultats n’ont pas objectivé une implication de l′ACEt dans l′interaction entre ovocyte et spermatozoïde et notamment dans la fixation à la ZP.
Published: 2013

16. Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage

Author: Paco Pino, Angelita Rebollo, Serge B. Assi, Zacharie Taoufiq, Issam Arrouss, Dominique Mazier, Florent Soubrier, Nadine N'dilimabaka, Immunité et Infection, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-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), Okinawa Institute of Science and Technology, Okinawa Institute of Science and Technology Graduate University (OIST), Department of Microbiology and Molecular Medicine, Université de Genève = University of Geneva (UNIGE), Institut Pierre Richet (IPR), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), ZT was financially supported by the Ministère de l'Education Nationale, de la Recherche et de la Technologie.and by la Fondation pour la Recherche Médicale (FRM)., Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Geneva [Switzerland], Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BMC, Ed., Service de Parasitologie - Mycologie [CHU Pitié-Salpétrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Atorvastatin, Pharmacology, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Endothelial Cells, Cells, Cultured, MESH: Plasmodium falciparum, 0303 health sciences, biology, Cell adhesion molecule, Pathophysiology, 3. Good health, Infectious Diseases, medicine.anatomical_structure, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Pyrroles, medicine.drug, MESH: Cells, Cultured, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, MESH: Heptanoic Acids, Plasmodium falciparum, 030231 tropical medicine, lcsh:Infectious and parasitic diseases, MESH: Cell Adhesion, MESH: Coculture Techniques, Antimalarials, 03 medical and health sciences, Cell Adhesion, medicine, Humans, Pyrroles, lcsh:RC109-216, 030304 developmental biology, MESH: Humans, Cholesterol, Research, Endothelial Cells, biology.organism_classification, MESH: Antimalarials, Coculture Techniques, Red blood cell, chemistry, Heptanoic Acids, Apoptosis, Immunology, Parasitology, Oxidative stress
Abstract: Background The adhesion of Plasmodium falciparum parasitized red blood cell (PRBC) to human endothelial cells (EC) induces inflammatory processes, coagulation cascades, oxidative stress and apoptosis. These pathological processes are suspected to be responsible for the blood-brain-barrier and other organs' endothelial dysfunctions observed in fatal cases of malaria. Atorvastatin, a drug that belongs to the lowering cholesterol molecule family of statins, has been shown to ameliorate endothelial functions and is widely used in patients with cardiovascular disorders. Methods The effect of this compound on PRBC induced endothelial impairments was assessed using endothelial co-culture models. Results Atorvastatin pre-treatment of EC was found to reduce the expression of adhesion molecules and P. falciparum cytoadherence, to protect cells against PRBC-induced apoptosis and to enhance endothelial monolayer integrity during co-incubation with parasites. Conclusions These results might suggest a potential interest use of atorvastatin as a protective treatment to interfere with the pathophysiological cascades leading to severe malaria.
Published: 2011
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17. Platelet protease nexin-1, a serpin that strongly influences fibrinolysis and thrombolysis

Author: Boulaftali, Yacine, Ho-Tin-Noe, Benoît, Pena, Ana, Loyau, Stéphane, Venisse, Laurence, François, Déborah, Richard, Benjamin, Arocas, Véronique, Collet, Jean-Philippe, Jandrot-Perrus, Martine, Bouton, Marie-Christine, Bouton, Marie-Christine, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by Inserm, Université Paris 7, and Fondation de France (grant 2009002497). Y.B. was supported by the Fondation pour la Recherche Médicale (FRM).
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, thrombolysis, platelets, fibrinolysis, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, serpinE2
Abstract: International audience; Background- Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma, but we have shown recently that PN-1 is present within the α-granules of platelets. Methods and Results- In this study, the role of platelet PN-1 in fibrinolysis was investigated with the use of human platelets incubated with a blocking antibody and platelets from PN-1-deficient mice. We showed by using fibrin-agar zymography and fibrin matrix that platelet PN-1 inhibited both the generation of plasmin by fibrin-bound tissue plasminogen activator and the activity of fibrin-bound plasmin itself. Rotational thromboelastometry and laser scanning confocal microscopy were used to demonstrate that PN-1 blockade or deficiency resulted in increased clot lysis and in an acceleration of the lysis front. Protease nexin-1 is thus a major determinant of the lysis resistance of platelet-rich clots. Moreover, in an original murine model in which thrombolysis induced by tissue plasminogen activator can be measured directly in situ, we observed that vascular recanalization was significantly increased in PN-1-deficient mice. Surprisingly, general physical health, after tissue plasminogen activator-induced thrombolysis, was much better in PN-1-deficient than in wild-type mice. Conclusions- Our results reveal that platelet PN-1 can be considered as a new important regulator of thrombolysis in vivo. Inhibition of PN-1 is thus predicted to promote endogenous and exogenous tissue plasminogen activator-mediated fibrinolysis and may enhance the therapeutic efficacy of thrombolytic agents.
Published: 2011
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18. Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy

Author: François Cambien, Anette Richter, Bernhard Maisch, Christa Zollbrecht, Laurence Tiret, Klaus Stark, Christa Meisinger, Jeanette Erdmann, Thomas Meitinger, Jean-Noël Trochu, Marie-Claude Aumont, Wolfgang Koenig, Laurent Fauchier, Arne Schillert, Peter Lichtner, Martina Grassl, Norman Klopp, Jens Baumert, Iris M. Heid, Vera Regitz-Zagrosek, Pascal DeGroote, Inke R. König, Philippe Charron, Patrick Linsel-Nitschke, Thomas Illig, Eric Villard, Roland Hetzer, Ulrike B. Esslinger, Thomas Wichter, Michel Komajda, Christian Hengstenberg, Thomas W. Winkler, Richard Isnard, Wibke Reinhard, H.-Erich Wichmann, Olivier Dubourg, Heribert Schunkert, George Petrov, Cardiovascular Sciences, 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), Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany, Universität Regensburg (UR), Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, WSB Neue Energien Gmbh, Partenaires INRAE, Cardiovascular Genomics, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique cardiovasculaire, Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Département de la Médecine, Université Paris Diderot - Paris 7 (UPD7), Hôpital Ambroise Paré [AP-HP], Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Philipps Universität Marburg = Philipps University of Marburg, and Universität Osnabrück - Osnabrück University
Subjects: Male, Cancer Research, Linkage disequilibrium, Cardiovascular Disorders/Heart Failure, HSP27 Heat-Shock Proteins, Bioinformatics, Gastroenterology, Polymerase Chain Reaction, Linkage Disequilibrium, [SHS]Humanities and Social Sciences, Gene Frequency, Risk Factors, Child, Genetics (clinical), Genetics and Genomics/Genetics of Disease, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, education.field_of_study, Middle Aged, Cardiovascular Disorders/Myopathies, Genetics and Genomics/Gene Discovery, Female, Research Article, Adult, Cardiomyopathy, Dilated, medicine.medical_specialty, Adolescent, Genotype, lcsh:QH426-470, Population, Single-nucleotide polymorphism, Biology, Genetics and Genomics/Complex Traits, Polymorphism, Single Nucleotide, Young Adult, Internal medicine, Idiopathic dilated cardiomyopathy, Genetics, medicine, SNP, Humans, Genetic Predisposition to Disease, ddc:610, education, Molecular Biology, Allele frequency, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Genetic association, Aged, Sequence Analysis, DNA, Minor allele frequency, lcsh:Genetics, Logistic Models, Case-Control Studies
Abstract: Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility., Author Summary Dilated cardiomyopathy is a severe disease of the heart muscle and often leads to chronic heart failure, eventually with the consequence of cardiac transplantation. Identification of genetic disease markers in at-risk persons could play an important role in preventive health care. Several mutations in familial forms of the disease are described. Here, we examine the role of common genetic variants on the sporadic form of dilated cardiomyopathy. By screening about 2,000 candidate genes previously related to cardiovascular disease in more than 1,900 cases and 3,600 controls, we show that a polymorphism in the HSPB7 gene (rs1739843) is strongly associated with susceptibility to dilated cardiomyopathy. We also show that the effect on disease risk is present in both German and French cohorts. Therefore, this study is an important step towards revealing insight in the genetic background of the sporadic form of dilated cardiomyopathy.
Published: 2010
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19. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1

Author: Marie-Christine Alessi, Mark Lathrop, Simon Heath, Diana Zelenika, Jessy Brocheton, Jean-François Schved, Marine Germain, Pilar Galan, Ewa Ninio, Stefan Blankenberg, Thomas Münzel, Joseph Emmerich, Irene D. Bezemer, Christine Biron-Andreani, François Cambien, Aurélien Delluc, Noémie Saut, Tanja Zeller, David-Alexandre Trégouët, Ludovic Drouet, Frits R. Rosendaal, Laurence Tiret, Pierre-Emmanuel Morange, Viviane Nicaud, Hervé Durand, Stefan-Martin Brand-Herrmann, Gwenaelle Burgos, Lance A. Bare, Gilles Pernod, 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), Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), 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), Service de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR6, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Department of Medicine II, Johannes Gutenberg - Universität Mainz (JGU), Hôpital de la Timone [CHU - APHM] (TIMONE), 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, Department of General and Interventional Cardiology, University Heart Center Hamburg, Risque Thrombotique et Mecanismes de l'Hemostase (U765), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-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) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), 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), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), 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), Risque Thrombotique et Mécanismes de l'Hémostase (U765), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, ThEMAS, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-IFR6, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Département de Médecine Interne et Pneumologie [Brest] ( DMIP - Brest ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Johannes Gutenberg-University Mainz, Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Risque Thrombotique et Mecanismes de l'Hemostase ( U765 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-IFR6, Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: MESH : Transcription Factors, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, MESH : Chromosomes, Human, Pair 6, 0302 clinical medicine, Genetics(clinical), Genetics (clinical), Genetics, Venous Thrombosis, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: Follow-Up Studies, MESH: Transcription Factors, MESH : Venous Thrombosis, MESH: Case-Control Studies, DNA-Binding Proteins, Chromosomes, Human, Pair 6, MESH : DNA-Binding Proteins, Erratum, MESH : Genome-Wide Association Study, MESH : Case-Control Studies, MESH: Chromosomes, Human, Pair 6, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Genetic determinism, 03 medical and health sciences, Report, Genetic predisposition, Humans, Genetic Predisposition to Disease, Allele, Gene, 030304 developmental biology, MESH: Humans, [ SDV ] Life Sciences [q-bio], MESH : Humans, linking inflammation protein atherothrombosis sequence risk, Case-control study, Chromosome, MESH : Follow-Up Studies, Case-Control Studies, MESH: Genome-Wide Association Study, MESH: Venous Thrombosis, MESH : Genetic Predisposition to Disease, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Follow-Up Studies, Genome-Wide Association Study, Transcription Factors
Abstract: International audience; To identify genetic susceptibility factors conferring increased risk of venous thrombosis (VT), we conducted a multistage study, following results of a previously published GWAS that failed to detect loci for developing VT. Using a collection of 5862 cases with VT and 7112 healthy controls, we identified the HIVEP1 locus on chromosome 6p24.1 as a susceptibility locus for VT. Indeed, the HIVEP1 rs169713C allele was associated with an increased risk for VT, with an odds ratio of 1.20 (95% confidence interval 1.13-1.27, p = 2.86 x 10(-9)). HIVEP1 codes for a protein that participates in the transcriptional regulation of inflammatory target genes by binding specific DNA sequences in their promoter and enhancer regions. The current results provide the identification of a locus involved in VT susceptibility that lies outside the traditional coagulation/fibrinolysis pathway.
Published: 2010
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20. Counter-regulation by atorvastatin of gene modulations induced by L-NAME hypertension is associated with vascular protection

Author: Liliane Louedec, Sophie Nadaud, Frédérique Capron, Florent Soubrier, Morgan Dupuis, Jean-Baptiste Michel, Isabelle Brocheriou, Mounsif Haloui, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Statin, Physiology, medicine.drug_class, Atorvastatin, [SDV]Life Sciences [q-bio], Nitric oxide, Biological pathway, chemistry.chemical_compound, Internal medicine, medicine, Animals, Pyrroles, Aorta, Pharmacology, biology, Cell growth, Transforming growth factor beta, Rats, Inbred F344, Rats, Nitric oxide synthase, Endocrinology, NG-Nitroarginine Methyl Ester, chemistry, Gene Expression Regulation, Heptanoic Acids, Hypertension, biology.protein, Molecular Medicine, Endothelium, Vascular, Intracellular, medicine.drug
Abstract: Statins, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, protect against deleterious effects of chronic nitric oxide inhibition. We aimed at determining the genes and pathways involved in the protective effect of statin treatment during hypertension. Chronic inhibition of nitric oxide synthesis by Nω-nitro- l -arginine methyl ester (L-NAME) induced accelerated hypertension which was slightly reduced by cotreatment with atorvastatin (100 mg/kg/day). Gene expression profile of aortic media was strongly modified by atorvastatin cotreatment which prevented modulation of many genes regulated by L-NAME administration (described in Dupuis, M., Soubrier, F., Brocheriou, I., Raoux, S., Haloui, M., Louedec, L., Michel, J.B., Nadaud, S., 2004. Profiling of aortic smooth muscle cell gene expression in response to chronic inhibition of nitric oxide synthase in rats. Circulation 110, 867–873). The functional classification of these genes highlighted several major biological pathways modulated in aortic media by atorvastatin: effectors involved in smooth muscle tone; extracellular matrix; intracellular mediators of cell proliferation. Moreover, atorvastatin partially prevented arterial wall thickening, TGF-β pathway activation, MCP-1 induction and smooth muscle cell proliferation induced by L-NAME treatment although blood pressure was only slightly reduced, suggesting mechanisms independent of blood pressure levels. The induction of PPARalpha mRNA expression by atorvastatin in L-NAME treated rats also suggests that this pathway could participate in the protective effect. In conclusion, our data show that atorvastatin specifically antagonizes a set of genes modulated by L-NAME-induced accelerated hypertension.
Published: 2009
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21. Molecular and functional characterization of polymorphisms in the secreted phospholipase A2 group X gene: relevance to coronary artery disease

Author: Gérard Lambeau, Claire Perret, Sonia-Athina Karabina, Sarah Gora, François Cambien, Ikram Jemel, Viviane Nicaud, Laurence Tiret, Ewa Ninio, Stefan Blankenberg, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS), Department of Medicine II, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), INSERM, FRM, ANR Progarm, CNRS, ARC, Université Nice Sophia Antipolis (... - 2019) (UNS), and Johannes Gutenberg - Universität Mainz (JGU)
Subjects: Untranslated region, Male, MESH: Group X Phospholipases A2, Fluoroimmunoassay, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, MESH: Fluoroimmunoassay, Coronary artery disease, 0302 clinical medicine, Genotype, Drug Discovery, MESH: Microscopy, Confocal, Genetics(clinical), CAD, MESH: Coronary Artery Disease, Genetics (clinical), Genetics, Medicine(all), MESH: Aged, 0303 health sciences, Microscopy, Confocal, MESH: Middle Aged, biology, MESH: Genetic Predisposition to Disease, Middle Aged, Immunohistochemistry, PLA2G10, MESH: Mutagenesis, Site-Directed, Molecular Medicine, MESH: 5' Untranslated Regions, Female, Original Article, Adult, Secreted phospholipase A2, 03 medical and health sciences, Phospholipase A2, MESH: Polymorphism, Genetic, medicine, Group X Phospholipases A2, Humans, Genetic Predisposition to Disease, Gene, 030304 developmental biology, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, MESH: Adult, MESH: Immunohistochemistry, medicine.disease, Molecular medicine, Human genetics, MESH: Male, biology.protein, Mutagenesis, Site-Directed, 5' Untranslated Regions, Polymorphisms, hGX sPLA2, MESH: Female
Abstract: International audience; Among secreted phospholipases A2 (sPLA2s), human group X sPLA2 (hGX sPLA2) is emerging as a novel attractive therapeutic target due to its implication in inflammatory diseases. To elucidate whether hGX sPLA2 plays a causative role in coronary artery disease (CAD), we screened the human PLA2G10 gene to identify polymorphisms and possible associations with CAD end-points in a prospective study, AtheroGene. We identified eight polymorphisms, among which, one non-synonymous polymorphism R38C in the propeptide region of the sPLA2. The T-512C polymorphism located in the 5' untranslated region was associated with a decreased risk of recurrent cardiovascular events during follow-up. The functional analysis of the R38C polymorphism showed that it leads to a profound change in expression and activity of hGX sPLA2, although there was no detectable impact on CAD risk. Due to the potential role of hGX sPLA2 in inflammatory processes, these polymorphisms should be investigated in other inflammatory diseases.
Published: 2009
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22. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease

Author: Tregouet, D., König, Inke, Erdemann, J., Munteanu, A., Braund, Peter, Hall, Alistair, Grohennig, A., Linsel-Nitschke, P., Perret, C., Desuremain, M., Meitinger, T., Wright, B., Preuss, M., Balmforth, A., Ball, S., Meisinger, C., Germain-Renaud, Cecile, Evans, A., Arveiller, D., Luc, G., Ruidavets, J.-B., Morrison, C., Van Der Harst, P., Schreiber, S., Neureuther, K., Schäfer, A., Bugert, P., El Mokhtari, N., Schrezenmeir, J., Stark, K., Rubin, D., Wichmann, H.-E., Hengstenberg, C., Ouwehand, W., Trust Case Control Consortium, Wellcome, Consortium, Cardiogenics, Ziegler, A., Tiret, L., Thompson, J., Cambien, François, Schunkert, Heribert, Samani, N., Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Genetics [Leicester], University of Leicester, Algorithmic number theory for cryptology (TANC), Laboratoire d'informatique de l'École polytechnique [Palaiseau] (LIX), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Machine Learning and Optimisation (TAO), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire d'informatique de l'École polytechnique [Palaiseau] (LIX), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Paris-Sud - Paris 11 (UP11)-Laboratoire de Recherche en Informatique (LRI), and Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec
Subjects: [INFO.INFO-DC]Computer Science [cs]/Distributed, Parallel, and Cluster Computing [cs.DC], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2009

23. G.P.13.05 Investigating the pathophysiology of SEPN1-related myopathy using gene expression microarrays

Author: Mathieu Rederstorff, S. Nadaud, Alain Lescure, Pascale Guicheney, Nigel F. Clarke, Alain Krol, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genetics, 0303 health sciences, Gene expression microarray, Biology, Pathophysiology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neurology (clinical), medicine.symptom, Myopathy, 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2008
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24. Common CX3CR1 alleles are associated with a reduced risk of headaches

Author: Combadière, Christophe, Godin, Ophelia, Vidal, Cécile, Cangialosi, Arnaud, Proust, Carole, Tzourio, Christophe, Service d'Immunologie [CHU Pitié-Salpétrière], 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), Immunologie cellulaire et tissulaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-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), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: MESH: Aged, MESH: Middle Aged, MESH: Humans, MESH: Alleles, MESH: Genetic Linkage, MESH: Headache, MESH: Follow-Up Studies, MESH: Migraine Disorders, MESH: Isoleucine, MESH: Male, MESH: Genotype, MESH: Neurogenic Inflammation, MESH: Risk Factors, MESH: Methionine, MESH: Polymorphism, Genetic, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Longitudinal Studies, MESH: Receptors, Chemokine, MESH: Female
Abstract: International audience; OBJECTIVES: The aim of this study was to investigate the role of the chemokine receptor CX3CR1 in headaches and migraine. METHODS: Distribution of 2 polymorphisms of the chemokine receptor CX3CR1 (V249I and T280M) was determined in a population-based sample of 1179 elderly individuals. RESULTS: Heterozygotes for both CX3CR1 polymorphisms had a reduced risk of recurrent headaches, with an odds ratio (OR) of 0.64 (95% confidence interval [CI] = 0.46-0.90) for the I249 allele and 0.55 (95% CI = 0.38-0.81) for the M280 allele. Haplotype analysis showed that carriers of the rarer CX3CR1 I249-M280 haplotype had a reduced risk of recurrent headaches, with an OR of 0.57 (95% CI = 0.41-0.80, P = .001). This association was seen for both nonmigraine headaches (OR = 0.47, 95% CI = 0.28-0.79, P = .004) and migraine (OR = 0.65, 95% CI = 0.43-0.98, P = .041). CONCLUSIONS: These results need to be replicated but suggest that the chemokine receptor CX3CR1 may play a role in recurrent headaches.
Published: 2008
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25. APOE genotype, ethnicity, and the risk of cerebral hemorrhage

Author: François Cambien, Stephen MacMahon, Christophe Tzourio, John Chalmers, Bruce Neal, Marie-Germaine Bousser, Stephen B. Harrap, Hisatomi Arima, Mark Woodward, Craig S. Anderson, Ophélia Godin, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Univ. Paris VII], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), The Georges Institute for International Health, The University of Sydney, Department of Environmental Medecine, Kyushu University [Fukuoka], Department of Physiology, University of Melbourne, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Kyushu University, and Tzourio, Christophe
Subjects: Apolipoprotein E, Male, Internationality, Apolipoprotein E2, Apolipoprotein E4, 030204 cardiovascular system & hematology, 0302 clinical medicine, Recurrence, Risk Factors, Genotype, Perindopril, Stroke, education.field_of_study, Incidence, Hazard ratio, Middle Aged, 3. Good health, Europe, Cohort studies, Association studies in genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Cerebral amyloid angiopathy, medicine.drug, medicine.medical_specialty, Population, 03 medical and health sciences, Apolipoproteins E, Asian People, Double-Blind Method, Internal medicine, Risk factors in epidemiology, medicine, Humans, Genetic Predisposition to Disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], cardiovascular diseases, education, Aged, Cerebral Hemorrhage, Intracerebral hemorrhage, Polymorphism, Genetic, business.industry, medicine.disease, Surgery, nervous system diseases, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: International audience; OBJECTIVE: The apolipoprotein E (APOE) polymorphism is an established risk factor for intracerebral hemorrhage (ICH) that is related to cerebral amyloid angiopathy in the white population. Among Asian populations, although ICH represents up to one third of all strokes and has high rates of mortality and morbidity, the role of the APOE polymorphism has not been well studied. METHODS: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, double-blind, placebo-controlled trial of a blood pressure lowering regimen in subjects with prior cerebrovascular disease. APOE status was determined for 5,671 patients, including 2,148 Asians (38%). RESULTS: During the 3.9 years of follow-up, ICH occurred in 99 patients. Overall, carrying an epsilon 2 or epsilon 4 allele of the APOE polymorphism was associated with an adjusted hazard ratio (HR(a)) of 1.85 (95% CI = 1.24 to 2.76). In Asian patients the risk of ICH for epsilon 2 or epsilon 4 carriers was 2.11 (95% CI = 1.28 to 3.47) and 1.48 (95% CI = 0.76 to 2.87) in Europeans. Carriers of the epsilon 2 or epsilon 4 allele had an increased risk of both incident and recurrent ICH, and both cortical and deep ICH, and most risk estimates were higher in Asians than in Europeans. For both ethnic groups and for subtypes of ICH active treatment more than halved the risk of ICH and the treatment effects were not different in carriers of the epsilon 2 or epsilon 4 allele and in those with the epsilon 3 epsilon 3 genotype. CONCLUSIONS: There is a strong association between APOE genotype and the risk of intracerebral hemorrhage (ICH). In Asian patients the role of APOE polymorphisms in ICH is much broader than was previously supposed.
Published: 2008
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26. Tests génétiques. Questions scientifiques, médicales et sociétales

Author: Ameisen , Jean-Claude, Cambien , Francois, Dervaux , Benoit, Douay , Sophie, GAUDILLIÈRE , Jean-Paul, Julian-Reynier , Claire, Rabeharisoa , Vololona, Roussey , Michel, Sobol , Hagay, Verstuyft , Celine, Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de recherches économiques et sociales (LABORES), Fédération Universitaire et Polytechnique de Lille, Université de Lille, Droit et Santé, CERMES - Centre de recherche Médecine, Science, Santé Société (CERMES - UMR 8169 / U750), Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie et Sciences Sociales Appliquées à l'Innovation Médicale, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Sociologie de l'Innovation i3 (CSI i3), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Département de médecine de l'enfant et de l'adolescent, hôpital Sud, Cancérologie (Inserm U599/IPC), Université de la Méditerranée - Aix-Marseille 2-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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut national de la santé et de la recherche médicale(INSERM), ORANGE, Colette, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut interdisciplinaire de l’innovation (I3), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de recherches économiques et sociales ( LABORES ), CERMES3 - Centre de recherche, médecine, sciences, santé, santé mentale, société ( CERMES3 - UM 7 (UMR 8211 / U988) ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -École des hautes études en sciences sociales ( EHESS ), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Sociologie de l'Innovation i3 ( CSI i3 ), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University ( PSL ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Sud, Cancérologie, Faculté de Médecine Saint‐Antoine, and Université Pierre et Marie Curie - Paris 6 ( UPMC )
Subjects: Susceptibilité génétique, Neurogénétique, [SDV.GEN]Life Sciences [q-bio]/Genetics, Tests génétiques, ADN, Analyse de génomes, Pharmacogénétique, Pathologies familiales, [SDV.GEN] Life Sciences [q-bio]/Genetics, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Prédisposition génétique
Abstract: Les progrès de la biologie moléculaire et les avancées des biotechnologies ont contribué à une augmentation rapide de l' offre de tests génétiques dans le domaine des maladies héréditaires. En France, près de 1 000 mala-dies héréditaires peuvent désormais faire l' objet d'un test diagnostique effectué dans le cadre d'une consultation de conseil génétique. Un programme de dépistage néonatal de cinq maladies génétiques existe depuis plu-sieurs années. Tous ces tests dans le domaine médical sont des actes intégrés dans le système de santé. Les avancées scientifiques et techniques permettent également de mettre en évidence des susceptibilités génétiques à des maladies multifactorielles (hyperten-sion, diabète,…). La mise à disposition du public de tests génétiques pour ces maladies soulève de nom-breuses questions éthiques et sociétales. À la demande de la Cnamts, l'Inserm a réalisé une expertise collective qui analyse les données scienti-fiques, médicales, éthiques, économiques, juridiques associées aux tests génétiques. Une large place est faite aux sciences humaines et sociales en particulier aux représentations collectives sur la santé et la maladie ainsi qu'à la relation médecin-patient. La question de la régulation de l'usage des tests génétiques est au coeur de cette expertise. Il s'agit d'un ouvrage qui sera utile aux décideurs poli-tiques et de santé publique ainsi qu'aux étudiants en génétique médicale, épidémiologie génétique, bio-éthique et aux professionnels en formation continue.
Published: 2008

27. Confirmation of associations between ion channel gene SNPs and QTc interval duration in healthy subjects

Author: Pascale Guicheney, Jean Tichet, Soraya Chaouch, Laetitia Gouas, Myriam Berthet, Anne Forhan, Beverley Balkau, Viviane Nicaud, Laurence Tiret, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut inter-Régional pour la SAnté (IRSA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Guicheney, Pascale
Subjects: Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Cohort Studies, Electrocardiography, 0302 clinical medicine, Ventricular Function, MESH: Cohort Studies, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, biology, MESH: Polymorphism, Single Nucleotide, Gene polymorphisms, KCNE2, ion channels, cardiovascular system, Female, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, MESH: Ventricular Function, medicine, Humans, cardiovascular diseases, Allele, education, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Haplotype, MESH: Haplotypes, MESH: Male, MESH: Electrocardiography, Minor allele frequency, Endocrinology, Haplotypes, MESH: Ion Channels, biology.protein, MESH: Female
Abstract: International audience; Population-based association studies have identified several polymorphic variants in genes encoding ion channel subunits associated with the electrocardiographic heart-rate-corrected QT (QTc) length in healthy populations of Caucasian origin (KCNH2 rs1,805,123 (K897 T) and rs3,815,459, SCN5A rs1,805,126 (D1,819D), 1,141-3 C>A, rs1,805,124 (H558R), and IVS24+116 G>A, KCNQ1 rs757,092, KCNE1 IVS2-128 G>A and rs1,805,127 (G38S), and KCNE2 rs2,234,916 (T8A)). However, few of these results have been replicated in independent populations. We tested the association of SNPs KCNQ1 rs757,092, KCNH2 rs3,815,459, SCN5A IVS24+116 G>A, KCNE1 IVS2-128 G>A and KCNE2 rs2,234,916 with QTc length in two groups of 200 subjects presenting the shortest and the longest QTc from a cohort of 2,008 healthy subjects. All polymorphisms were in Hardy-Weinberg equilibrium in both groups. The minor allele SCN5A IVS24+116 A was more frequent in the group of subjects with the shortest QTc, whereas the minor alleles KCNQ1 rs757,092 G and KCNH2 rs3,815,459 A were more frequent in the group with the longest QTc. There was no significant difference for KCNE1 IVS2-128 G>A and KCNE2 rs2,234,916 between the two groups. Haplotype analysis showed a twofold increased risk of QTc lengthening for carriers of the haplotype, combining alleles C and A of the two common KCNE1 SNPs, IVS2-129 C>T (rs2,236,609) and rs1,805,127 (G38S), respectively. In conclusion, our study confirms the reported associations between QTc length and KCNQ1 rs757,092 and KCNH2 rs3,815,459.
Published: 2007
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28. Fetal and maternal CYP2E1 genotypes and the risk of nonsyndromic oral clefts

Author: Agnès Nelva, Michel Bahuau, Claire Perret, Elisabeth Robert-Gnansia, Sylvaine Cordier, Cécile Chevrier, Christine Francannet, Christine Herman, Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-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), Registre des Malformations Rhône-Alpes, REMERA, Centre d'Etude des Malformations Congénitales (CEMC), Centre d'Etude des Malformations Congénitales, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Oral cavity, MESH: Risk Assessment, MESH: Genotype, Gene Frequency, Polymorphism (computer science), Genotype, MESH: Maternal Exposure, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Obstetrics, 030305 genetics & heredity, Smoking, MESH: Genetic Predisposition to Disease, Cytochrome P-450 CYP2E1, Congenital cleft, MESH: Infant, Cleft Palate, Maternal Exposure, Female, Risk assessment, Adult, medicine.medical_specialty, MESH: Smoking, Alcohol Drinking, Cleft Lip, Risk Assessment, 03 medical and health sciences, Internal medicine, MESH: Polymorphism, Genetic, Genetics, medicine, MESH: Gene Frequency, Humans, Genetic Predisposition to Disease, Risk factor, Allele frequency, 030304 developmental biology, Fetus, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, business.industry, MESH: Cleft Lip, Infant, MESH: Adult, MESH: Male, Endocrinology, MESH: Cleft Palate, MESH: Cytochrome P-450 CYP2E1, business, MESH: Female, MESH: Alcohol Drinking
Abstract: International audience
Published: 2007
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29. Melatonin counteracts the loss of agonist-evoked contraction of aortic rings induced by incubation

Author: Aurore Tabellion, Christine Capdeville-Atkinson, Angela C. Resende, Sebastien Faure, Jeffrey Atkinson, Denyse Bagrel, Sophie Nadaud, I. Lartaud, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Contraction (grammar), [SDV]Life Sciences [q-bio], Nitric Oxide Synthase Type II, Aorta, Thoracic, In Vitro Techniques, Melatonin receptor, Nitric oxide, Melatonin, Norepinephrine, chemistry.chemical_compound, medicine.artery, Internal medicine, medicine, Animals, Vasoconstrictor Agents, Pharmacology (medical), RNA, Messenger, Rats, Wistar, Pharmacology, Glutathione Peroxidase, Aorta, biology, Catalase, Culture Media, Rats, Nitric oxide synthase, Endocrinology, chemistry, biology.protein, medicine.symptom, Luzindole, Vasoconstriction, medicine.drug
Abstract: Incubation of aortic rings in a culture medium produces phenomena similar to those observed with aging, i.e. oxidative stress and inflammation leading to increased nitric oxide (NO)-mediated dilation and decreased arterial sensitivity to vasoconstrictor agents. We evaluated whether melatonin protects aortic rings from such a decrease in vasoreactivity. Two concentrations of melatonin were used: 10(-8) M, EC50 for vascular MT1-MT2 receptors, and 10(-5) M, reported as anti-oxidant. Anti-oxidant capacity, inducible nitric oxide synthase (iNOS) expression and isometric contraction of thoracic aorta rings (Wistar rats) evoked by norepinephrine (NE) were assessed. Three days of incubation of aortic rings induced iNOS expression and a fall in NE-evoked contraction. When melatonin was added to the organ bath, it (10(-5) M) increased (+96%, P0.05), but did not restore (compared with freshly isolated rings) NE-evoked contraction. Three days of treatment with melatonin increased (10(-8) M, +99%) or restored (10(-5) M, +216%) NE-evoked contraction (compared with freshly isolated rings). The beneficial effects of 10(-8) and 10(-5) M melatonin on NE-evoked contraction were abolished in the presence of luzindole (2 x 10(-6) M, a melatonin receptor antagonist). The incubation-induced increase in iNOS expression was reduced following 3 days of melatonin administration (10(-8) and 10(-5) M). Melatonin (10(-5) M) increased catalase activity (6550 +/- 256, P0.05 vs. nontreated fresh aortic rings 5554 +/- 444 nmol min(-1) mg protein(-1)). In conclusion, melatonin counteracts the incubation-induced loss of agonist-evoked contraction of aortic rings by a specific receptor-mediated phenomenon involving iNOS expression; at higher melatonin concentrations, an anti-oxidant effect is probably also involved.
Published: 2007
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30. [Present possibilities and future development of clinical proteomics]

Author: Lehmann, Sylvain, Dupuy, A., Peoc'H, K., Roche, Stephane, Baudin, B., Beaudeux, J.-L., Quillard, M., Berger, F., Briand, G., Chwetzoff, S., Dine, G., Gonzalo, P., Roche, Stéphane, Dastugue, B., Seve, M., Siest, G., Larose, Catherine, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Lapeyronie [Montpellier] (CHU), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], CHU Rouen, Normandie Université (NU), Neurosciences précliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Inflammation intestinale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Centrale Paris, Bases moléculaires et structurales des systèmes infectieux (BMSSI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), CIC - Biotherapie - Lyon - Grenoble, Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Proteomics, Protein Array Analysis, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Microfluidic Analytical Techniques, Gas Chromatography-Mass Spectrometry, multiplex, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, biomarker, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Electrophoresis, Gel, Two-Dimensional, protéomique, biomarqueur, Biomarkers, Forecasting
Abstract: This review focuses on "clinical proteomics" which represents an emerging discipline in biomedical research. "Clinical proteomics" relies on the analysis of the proteome, i.e. the entire set of peptides and proteins present in a biological sample, to provide relevant data for diagnosis, prognosis or therapeutic strategies of human pathologies. This new type of approach has tremendous potential for the diagnosis of complex pathologies or for the early detection of cancers. This article reports the conclusions of a workgroup of the French Society for Clinical Biology (SFBC) 2004-2006 which evaluated the status, the impact and the future development of proteomics in the clinical field. It provides therefore a broad view going from the methods already present in the clinical laboratories (multiplex technologies...), to the tools for clinical and basis research including bioinformatics., Cet article de synthèse se penche sur une nouvelle discipline biologique et médicale, la « protéomique clinique ». Cette approche « post-génomique » vise à utiliser l’étude du protéome, c’est-à-dire de l’ensemble des peptides et protéines présents dans un échantillon biologique, pour donner une information diagnostique, pronostique ou de suivi thérapeutique des pathologies humaines. Cette nouvelle discipline est en plein développement car elle présente d’importantes perspectives pour les pathologies complexes ou pour la détection précoce de pathologies telles que les cancers. Les éléments de cette revue résultent du travail d’un groupe thématique de la SFBC (Société française de biologie clinique) de 2004 à 2006 dont l’objectif était d’évaluer l’état actuel de la « protéomique clinique » et de s’interroger sur son développement et son application future pour les biologistes. Il s’agit donc d’un état des lieux assez large décrivant les approches déjà accessibles dans les laboratoires d’analyses biologiques (dosages multiplex…) et les outils disponibles en recherche clinique et en protéomique « fondamentale », sans oublier les aspects bio-informatiques nécessaires à l’utilisation des données générées.
Published: 2007
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31. Genetic variations at the endocannabinoid type 1 receptor gene (CNR1) are associated with obesity phenotypes in men

Author: Alfonso Siani, David A. Tregouet, Marco Versiero, Pasquale Strazzullo, M. Loguercio, Gianvincenzo Barba, Francesco P. Cappuccio, Fabio Lauria, Paola Russo, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Epidemiology & Population Genetics, Institute of Food Sciences, Department of Clinical and Experimental Medicine, 'Federico II' University of Naples Medical School, Clinical Science Research Institute, Warwick Medical School, University of Warwick [Coventry]-University of Warwick [Coventry], The OPHS was supported in part by MIUR (Italian Ministry of University and Research, COFIN 2004 and FIRB 2001). The WHSS has received support from the Wandsworth Health Authority, the South West Thames Regional Health Authority, the NHS R&D Directorate, the British Heart Foundation, the British Diabetic Association, and The Stroke Association., Simon, Marie Francoise, Russo, P, Strazzullo, Pasquale, Cappuccio, Fp, Tregouet, Da, Lauria, F, Loguercio, M, Barba, G, Versiero, Marco, and Siani, A.
Subjects: Male, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, MESH: Receptor, Cannabinoid, CB1, Biochemistry, MESH: Genotype, 0302 clinical medicine, Endocrinology, Rimonabant, Gene Frequency, Receptor, Cannabinoid, CB1, Polymorphism (computer science), MESH: Risk Factors, Risk Factors, MESH: Obesity, Body Fat Distribution, MESH: Genetic Variation, 2. Zero hunger, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: European Continental Ancestry Group, Middle Aged, Endocannabinoid system, 3. Good health, Phenotype, medicine.drug, medicine.medical_specialty, Genotype, 030209 endocrinology & metabolism, Context (language use), Single-nucleotide polymorphism, Biology, MESH: Phenotype, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Internal medicine, medicine, MESH: Gene Frequency, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Body Fat Distribution, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Predisposition to Disease, Obesity, 030304 developmental biology, Aged, Retrospective Studies, MESH: Humans, Biochemistry (medical), Genetic Variation, MESH: Retrospective Studies, Anthropometry, medicine.disease, MESH: Male, Cannabinoid
Abstract: Context: The endocannabinoid system modulates food intake and body weight in animal models. Treatment with the cannabinoid type 1 receptor blocker, rimonabant, reduces body weight in obese individuals. Objective: The aim of this study was to determine whether single nucleotide polymorphisms of the gene encoding cannabinoid type 1 receptor, CNR1, are associated with body fat mass and distribution in two independent samples of white European adult men. Design, Setting, and Participants: The 3813A/G and 4895A/G single nucleotide polymorphisms at the exon 4 of CNR1 were genotyped in 930 participants to the Olivetti Prospective Heart Study (OPHS) in Southern Italy and in 216 participants to the Wandsworth Heart and Stroke Study in the United Kingdom. Retrospective analysis was also performed on an OPHS subsample (n = 360) for which anthropometric data from 1987 and 1994–1995 examinations were available. Main Outcome Measures: CNR1 genotypes and anthropometric measures of body fat distribution were determined. Results: In the OPHS study, the 3813G allele was associated with increased subscapular skinfold thickness (24.2 ± 9.1 vs. 22.8 ± 7.7 mm; P = 0.031) and waist circumference (WC) (99.1 ± 8.8 vs. 97.7 ± 8.8 cm; P = 0.050). No association was observed with 4895A/G variant. Haplotype analysis confirmed that the unique haplotype carrying the 3813G was associated with increased WC and subscapular skinfold thickness. Similar results were observed in the OPHS retrospective subsample and the Wandsworth Heart and Stroke Study sample. In the latter, the 3813G was associated with increased WC (96.8 ± 11.3 vs. 91.6 ± 10.4 cm; P = 0.006). Conclusions: Genetic variants at CNR1 are associated with obesity-related phenotypes in men. The detection of polymorphic variants in genes involved in the process of fat accumulation may help identify specific targets for pharmacological treatment of obesity and related metabolic abnormalities.
Published: 2007
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32. Atherogenic properties of LDL particles modified by human group X secreted phospholipase A2 on human endothelial cell function

Author: Sonia‐Athina Karabina, Isabelle Brochériou, Gilles Le Naour, Monique Agrapart, Hervé Durand, Michael Gelb, Gérard Lambeau, Ewa Ninio, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Departements of Chemistry and Biochemistry, Seattle University [Seattle], Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), INSERM, Marie Curie Individual Fellowship, FRM, CNRS, ARC, NIHG, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: 030204 cardiovascular system & hematology, Biochemistry, MESH: Atherosclerosis, chemistry.chemical_compound, 0302 clinical medicine, MESH: Endothelial Cells, 0303 health sciences, biology, Cell adhesion molecule, Arteries, Endothelial stem cell, Protein Transport, Low-density lipoprotein, MESH: Cell Adhesion Molecules, MESH: Phospholipases A, Biotechnology, MESH: Cholesterol, LDL, MESH: Protein Transport, Phospholipid, Phospholipases A, Cell Line, Veins, MESH: Cell Adhesion, 03 medical and health sciences, Phospholipase A2, Genetics, Cell Adhesion, Group X Phospholipases A2, Humans, RNA, Messenger, Cell adhesion, Molecular Biology, MESH: Arteries, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, MESH: Veins, Cholesterol, Macrophages, Endothelial Cells, MESH: Macrophages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cholesterol, LDL, Atherosclerosis, MESH: Cell Line, Phospholipases A2, chemistry, biology.protein, Cell Adhesion Molecules, Lipoprotein
Abstract: Increasing evidence suggests that secreted phospholipases A2 (sPLA2s) play an important role in the pathophysiology of atherosclerosis. Among sPLA2s, the human group X (hGX) enzyme has the highest catalytic activity toward phosphatidylcholine, one of the major phospholipid species of cell membranes and low-density lipoprotein (LDL). Our study examined the presence of hGX sPLA2 in human atherosclerotic lesions and investigated the ability of hGX modified LDL to alter human endothelial cell (HUVEC) function. Our results show that hGX sPLA2 is present in human atherosclerotic lesions and that the hydrolysis of LDL by hGX sPLA2 results in a modified particle that induces lipid accumulation in human monocyte-derived macrophages. Acting on endothelial cells, hGX-modified LDL activates the MAP kinase pathway, which leads to increased arachidonic acid release, increased expression of adhesion molecules on the surface of HUVEC, and increased adhesion of monocytes to HUVEC monolayers. Together, our data suggest that LDL modified by hGX, rather than hGX itself may have strong proinflammatory and proatherogenic properties, which could play an important role in the propagation of atherosclerosis.
Published: 2006
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33. The proinflammatory mediator Platelet Activating Factor is an effective substrate for human group X secreted phospholipase A2

Author: James G. Bollinger, Sarah Gora, Michael H. Gelb, Gérard Lambeau, Ewa Ninio, Sonia Karabina, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Washington [Seattle], INSERM, FRM, MESR, CNRS, ARC, NIHG, and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: MESH: Lipoproteins, LDL, Swine, Phospholipid, Phospholipases A, Group V Phospholipases A2, Substrate Specificity, Proinflammatory cytokine, MESH: Recombinant Proteins, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Phospholipase A2, Phosphatidylcholine, Extracellular, Animals, Group X Phospholipases A2, Humans, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Platelet Activating Factor, Molecular Biology, MESH: Swine, 030304 developmental biology, 0303 health sciences, Phospholipase A, MESH: Platelet Activating Factor, MESH: Humans, biology, Platelet-activating factor, Chemistry, Hydrolysis, Biological activity, Cell Biology, respiratory system, MESH: Phosphatidylcholines, Recombinant Proteins, 3. Good health, Lipoproteins, LDL, Phospholipases A2, Biochemistry, 030220 oncology & carcinogenesis, Phosphatidylcholines, biology.protein, lipids (amino acids, peptides, and proteins), MESH: Phospholipases A, MESH: Substrate Specificity, MESH: Hydrolysis
Abstract: Platelet Activating Factor (PAF) is a potent mediator of inflammation whose biological activity depends on the acetyl group esterified at the sn-2 position of the molecule. PAF-acetylhydrolase (PAF-AH), a secreted calcium-independent phospholipase A(2), is known to inactivate PAF by formation of lyso-PAF and acetate. However, PAF-AH deficient patients are not susceptible to the biological effects of inhaled PAF in airway inflammation, suggesting that other enzymes may regulate extracellular levels of PAF. We therefore examined the hydrolytic activity of the recently described human group X secreted phospholipase A(2) (hGX sPLA(2)) towards PAF. Among different sPLA(2)s, hGX sPLA(2) has the highest affinity towards phosphatidylcholine (PC), the major phospholipid of cellular membranes and plasma lipoproteins. Our results show that unlike group IIA, group V, and the pancreatic group IB sPLA(2), recombinant hGX sPLA(2) can efficiently hydrolyze PAF. The hydrolysis of PAF by hGX sPLA(2) rises abruptly when the concentration of PAF passes through its critical micelle concentration suggesting that the enzyme undergoes interfacial binding and activation to PAF. In conclusion, our study shows that hGX sPLA(2) may be a novel player in PAF regulation during inflammatory processes.
Published: 2006
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34. Vers l'extraction de motifs rares

Author: Szathmary, Laszlo, Maumus, Sandy, Pierre, Petronin, Toussaint, Yannick, Napoli, Amedeo, Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale de la Statistique et de l'Analyse de l'Information [Bruz] (ENSAI), and Gilbert Ritschard, Chabane Djeraba
Subjects: [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], [INFO.INFO-IR]Computer Science [cs]/Information Retrieval [cs.IR], [INFO.INFO-DS]Computer Science [cs]/Data Structures and Algorithms [cs.DS], rare itemset search, ACM: I.: Computing Methodologies/I.2: ARTIFICIAL INTELLIGENCE/I.2.6: Learning
Abstract: National audience; Un certain nombre de travaux en fouille de données se sont intéressés à l'extraction de motifs et à la génération de règles d'association à partir de ces motifs. Cependant, ces travaux se sont jusqu'à présent, centrés sur la notion de motifs fréquents. Le premier algorithme à avoir permis l'extraction de tous les motifs fréquents est Apriori mais d'autres ont été mis au point par la suite, certains n'extrayant que des sous-ensembles de ces motifs (motifs fermés fréquents, motifs fréquents maximaux, générateurs minimaux). Dans cet article, nous nous intéressons aux motifs rares qui peuvent également véhiculer des informations importantes. Les motifs rares correspondent au complémentaire des motifs fréquents. A notre connaissance, ces motifs n'ont pas encore été étudiés, malgré l'intérêt que certains domaines pourraient tirer de ce genre de modèle. C'est en particulier le cas de la médecine, où par exemple, il est important pour un praticien de repérer les symptômes non usuels ou les effets indésirables exceptionnels qui peuvent se déclarer chez un patient pour une pathologie ou un traitement donné.
Published: 2006

35. Platelet-activating factor increases VE-cadherin tyrosine phosphorylation in mouse endothelial cells and its association with the PtdIns3'-kinase

Author: Dominique Stengel, Ewa Ninio, Isabelle Vilgrain, Hélène Hudry-Clergeon, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by INSERM (EMI 02-19 and U525), Commissariat à l'Energie Atomique, Direction des Sciences du Vivant/ Département Réponse Dynamique Cellulaire/ Association pour la Recherche contre le Cancer (ARC#5588), Fédération Nationale des Centres de Lutte contre le Cancer, Fondation pour la Recherche Médicale, and Ligue Nationale contre le Cancer., Huber, Philippe, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: PtdIns3'- kinase, Endothelial cells, Fluorescent Antibody Technique, Protein tyrosine phosphatase, MESH: Receptors, G-Protein-Coupled, Biochemistry, adherens junction, Receptor tyrosine kinase, MESH: Cadherins, Receptors, G-Protein-Coupled, MESH: Tyrosine, MESH: Benzoquinones, chemistry.chemical_compound, Mice, Phosphatidylinositol 3-Kinases, angiogenesis, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Benzoquinones, MESH: Animals, MESH: Endothelial Cells, Enzyme Inhibitors, Phosphorylation, MESH: Fluorescent Antibody Technique, MESH: Antigens, CD, Immunosorbent Techniques, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Quinones, Heart, Adherens Junctions, Protein-Tyrosine Kinases, Tyrphostins, Cadherins, Cell biology, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, Tyrosine kinase, MESH: Mitogen-Activated Protein Kinase 3, Platelet-derived growth factor receptor, Biotechnology, Proto-oncogene tyrosine-protein kinase Src, MESH: Mitogen-Activated Protein Kinase 1, platelet-activating factor, MESH: Enzyme Activation, Lactams, Macrocyclic, Platelet Membrane Glycoproteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Protein-Tyrosine Kinases, Article, MESH: Quinones, Cell Line, Adherens junction, 03 medical and health sciences, Antigens, CD, MESH: Intracellular Signaling Peptides and Proteins, Genetics, Animals, RNA, Messenger, Platelet Activating Factor, MESH: Tyrphostins, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, VE cadherin, MESH: Immunosorbent Techniques, 030304 developmental biology, MESH: RNA, Messenger, MESH: Platelet Activating Factor, MESH: Phosphorylation, Akt, MESH: Embryo, Mammalian, MESH: Platelet Membrane Glycoproteins, Tyrosine phosphorylation, MESH: Lactams, Macrocyclic, MESH: 1-Phosphatidylinositol 3-Kinase, Embryo, Mammalian, FLT4, MESH: Cell Line, Enzyme Activation, MESH: Heart, MESH: Adherens Junctions, chemistry, Rifabutin, biology.protein, Tyrosine
Abstract: International audience; Platelet-activating factor (PAF), a potent inflammatory mediator, is involved in endothelial permeability. This study was designed to characterize PAF receptor (PAF-R) expression and its specific contribution to the modifications of adherens junctions in mouse endothelial cells. We demonstrated that PAF-R was expressed in mouse endothelial cells and was functionally active in stimulating p42/p44 MAPK and phosphatidylinositol 3-kinase (PtdIns3'-kinase)/Akt activities. Treatment of cells with PAF induced a rapid time- and dose-dependent (10(-7) to 10(-10) M) increase in tyrosine phosphorylation of a subset of proteins ranging from 90 to 220 kDa, including the VE-cadherin, the latter effect being prevented by the tyrosine kinase inhibitors herbimycin A and bis-tyrphostin. We demonstrated that PAF promoted formation of multimeric aggregates of VE-cadherin with PtdIns3'-kinase, which was also inhibited by herbimycin and bis-tyrphostin. Finally, we show by immunostaining of endothelial cells VE-cadherin that PAF dissociated adherens junctions. The present data provide the first evidence that treatment of endothelial cells with PAF promoted activation of tyrosine kinases and the VE-cadherin tyrosine phosphorylation and PtdIns3'-kinase association, which ultimately lead to the dissociation of adherens junctions. Physical association between PtdIns3'-kinase, serving as a docking protein, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of PAF-induced cellular activation.
Published: 2005
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36. Exploitation des données de la cohorte STANISLAS par des techniques de fouille de données numériques et symboliques utilisées seules ou en combinaison

Author: Sandy Maumus, Amedeo Napoli, Laszlo Szathmary, Sophie Visvikis-Siest, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), and Vidard, Agnès
Subjects: motif fréquent, données complexes, syndrome métabolique, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], [INFO.INFO-IR]Computer Science [cs]/Information Retrieval [cs.IR], [INFO.INFO-DS]Computer Science [cs]/Data Structures and Algorithms [cs.DS], règle d'association, [INFO.INFO-DS] Computer Science [cs]/Data Structures and Algorithms [cs.DS], [INFO.INFO-IR] Computer Science [cs]/Information Retrieval [cs.IR], [INFO.INFO-LG] Computer Science [cs]/Machine Learning [cs.LG], arbre de décision, fouille de données
Abstract: La cohorte STANISLAS est une population de familles d'origine française supposées saines, recrutées au Centre de Médecine Préventive de Vandoeuvre-lès-Nancy et suivies tous les cinq ans sur une période de dix ans. Les données de la cohorte, de types numérique et textuel, représentent une richesse et un volume considérables, exploitées jusque là par des méthodes statistiques classiques. Nous proposons d'étudier ces données par des techniques de fouille de données numériques et symboliques, en nous intéressant plus exactement à l'étude du syndrome métabolique dans la cohorte STANISLAS, une affection correspondant à la présence simultanée chez un individu de plusieurs facteurs de risques cardiovasculaires. Nous présentons ici nos recherches en cours sur ce domaine, qui font intervenir l'utilisation de la boîte à outils Weka et de J-Close, une implémentation en Java d'un algorithme d'extraction de motifs fréquents et de règles d'association. Ultérieurement nous projetons le couplage d'un module de classification de Weka avec J-Close.
Published: 2005

37. Biological variations, genetic polymorphisms and familial resemblance of TNF-alpha and IL-6 concentrations: STANISLAS cohort

Author: Suzanne Droesch, Nadia Haddy, Sophie Visvikis, Catherine Sass, Sandy Maumus, Daniel Lambert, Bérangère Marie, Gérard Siest, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, l'Institut national de la santé et de la recherche médicale (INSERM), Ministère de la Santé et de la Recherche, Centre du Médicament [Nancy], and Université Henri Poincaré - Nancy 1 (UHP)
Subjects: Male, Arteriosclerosis, Overweight, MESH: Variation (Genetics), Cohort Studies, MESH: Genotype, 0302 clinical medicine, Polymorphism (computer science), Genotype, Longitudinal Studies, 10. No inequality, MESH: Longitudinal Studies, MESH: Cohort Studies, Genetics (clinical), 0303 health sciences, MESH: Middle Aged, Middle Aged, Cohort, Female, France, medicine.symptom, MESH: Cholesterol, HDL, Cohort study, Adult, medicine.medical_specialty, Adolescent, Offspring, Biology, 03 medical and health sciences, Age Distribution, Internal medicine, Genetic variation, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, Allele, MESH: Age Distribution, 030304 developmental biology, MESH: Adolescent, Polymorphism, Genetic, MESH: Humans, Interleukin-6, Tumor Necrosis Factor-alpha, Body Weight, Cholesterol, HDL, Genetic Variation, MESH: Adult, MESH: Interleukin-6, MESH: Male, MESH: Body Weight, MESH: France, Endocrinology, MESH: Arteriosclerosis, MESH: Tumor Necrosis Factor-alpha, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female, 030217 neurology & neurosurgery
Abstract: Cytokines are involved in the development of several inflammatory diseases and atherosclerosis. Their variations in healthy individuals are not well defined. The aims of this study were: firstly, to identify factors affecting biological variation of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha); secondly, to study their family resemblance; and thirdly, to evaluate the effect of two TNF-alpha (-308G/A and -238G/A) and two IL-6 polymorphisms (174G/C and -572G/C) on their corresponding circulating levels. A total of 171 healthy families selected from the STANISLAS cohort were studied. Age was negatively related to TNF-alpha concentrations in offspring only (both sons and daughters). Additionally, IL-6 and TNF-alpha levels were differently influenced by gender, white blood cells, tobacco consumption, and HDL-cholesterol level. A weak significant familial resemblance for TNF-alpha concentration was observed in siblings only. There was no significant familial resemblance for IL-6 levels. The TNF-alpha -308A allele was associated with decreased TNF-alpha concentrations in both offspring aged less than 18 and males without overweight (BMI
Published: 2005
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38. Towards a global methodology for mining cohorts with biological and genetic data

Author: Sandy Maumus, Laszlo Szathmary, Amedeo Napoli, Eliane Albuisson, Sophie Visvikis-Siest, Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), and Contrat de Plan Etat-Région, PRST Intelligence Logicielle
Subjects: frequent pattern extraction, association rules, biomedical data mining, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: Objective: Biomedical data collected in cohorts are rather complex to analyse because of their diversity and their size. This paper introduces an expert-guided methodology for extensively mining such data. For this specific study, the expert is interested in extracting profiles showing the co-occurrence of biological parameters with specific genetic polymorphisms. Methods and materials: Experiments have been performed with CORON, a data mining platform which has been design to fit the methodology. CORON proposes symbolic data mining methods, i.e. frequent pattern search and association rule extraction. The results found with the methodology have been validated by statistical tests. The used real data stem from the STANISLAS cohort, a population study composed of information that has been collected in healthy French families for ten years. As the STANISLAS cohort is composed of healthy individuals, the methodology described here is oriented for extracting less frequent patterns. Results: In this paper, two study frameworks illustrate the methodology. The first one (framework #1) deals with interactions involving lipids. The second one (framework #2) concerns the metabolic syndrome. Some results are reported thereafter. In framework #1, in men, a significant interaction was found between BMI>25 and APOB Thr71Ile polymorphism on LDL-cholesterol concentration (p=0.009). In women, we detected a potential protective genetic profile against cardiovascular diseases involving an interaction between APOE and APOB genes (p=0.016). In framework #2, the repartition of genotypes of the APOB71 polymorphism is significantly different whether an individual presents metabolic syndrome or not (p=0.03). Conclusion: The obtained results show the capabilities of the data mining methodology, performed with CORON, for suggesting new biological hypotheses to the expert which deserve to be further analysed by larger genetic epidemiology studies or wet laboratory experiments.
Published: 2005

39. Fouille de données biomédicales complexes : extraction de règles et de profils génétiques dans le cadre de l'étude du syndrome métabolique

Author: Sandy Maumus, Amedeo Napoli, Laszlo Szathmary, Sophie Visvikis-Siest, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), contrat de plan Etat-Région, G. Perrière, A. Guénoche, C. Gourgeon, Maumus, Sandy, and G. Perrière, A. Guénoche, C. Gourgeon
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], Règle d'association, Polymorphisme génétique, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Syndrome métabolique, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Motif fréquent
Abstract: 5 pages; Nous décrivons une étude sur la fouille de données de la cohorte STANISLAS qui met en œuvre l'extraction de motifs fréquents et de règles d'association. D'une part, nous avons extrait des connaissances utiles et nouvelles pour l'expert qui lui ont permis de générer de nouvelles hypothèses de recherche en biologie. D'autre part, ces travaux nous ont conduit à proposer les premiers éléments d'une méthodologie de fouille de règles extraites en bioinformatique. Au cœur de ces réflexions, nous soulignons le rôle majeur de l'expert dans le processus de fouille de données. Les résultats obtenus sont satisfaisants et illustrent le potentiel des méthodes symboliques de fouille de données en biologie.
Published: 2005

40. Polymorphism of the 5-HT2A receptor gene and food intakes in children and adolescents: the Stanislas Family Study

Author: Frédéric Cailotto, Bernard Herbeth, Frédéric Fumeron, Roberte Aubert, Eléonore Aubry, Gérard Siest, Sophie Visvikis-Siest, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Adult, Male, Food intake, medicine.medical_specialty, Adolescent, Cross-sectional study, Saturated fat, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Eating, 0302 clinical medicine, Internal medicine, Genotype, medicine, Humans, Receptor, Serotonin, 5-HT2A, Allele, Child, Promoter Regions, Genetic, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Polymorphism, Genetic, Nutrition and Dietetics, Cross-Sectional Studies, Endocrinology, El Niño, Etiology, Female, Gene polymorphism
Abstract: Background: Serotonin (5-hydroxytryptamine; 5-HT) is a key mediator in the control of food intake and is probably involved in the etiology of anorexia nervosa. An association between a polymorphism of the 5-HT receptor (5-HT 2A ) gene promoter (- 1438G/A) and anorexia nervosa has been reported. Objective: We investigated the relation between the -1438G/A polymorphism of the 5-HT 2A gene and the energy and macronutrient intakes of children and adolescents. Design: This cross-sectional study included 370 children and adolescents aged 10-20 y (176 boys and 194 girls from 251 families) drawn from the Stanislas Family Study. Energy and macronutrient intakes were assessed by using 3-d food records. The -1438G/A polymorphism was analyzed by polymerase chain reaction and then by Hpa II digestion. Results: In the overall group, after adjustment for age, sex, weight, height, and family correlation, the A allele was significantly associated with lower energy (P for trend = 0.045) and with total, mono-unsaturated, and saturated fat intakes expressed in g/d (P for trend = 0.007, 0.005, and 0.006, respectively). Subjects with the GA genotype had intermediate values. In addition, genotype X sex and genotype X age interactions were not significant. Conclusions: The 5-HT 2A gene polymorphism in the promoter region is associated with energy and fat intakes in young people. This could be explained by the role of the serotonergic system as a determinant of food intakes and eating behavior.
Published: 2005
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41. Cytochromes P450 and vascular tone

Author: Thiebault, Céline, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Henri Poincaré - Nancy I, Anne Marie Batt, and Thiebault, Céline
Subjects: [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, statines, tonus vasculaires, saphenous veins, polymorphisme, vascular tone, veines saphènes, Cytochromes P450, statins
Abstract: The cytochromes P450 (CYP) are enzymes whose mainly known role is detoxification. However, their activity can lead to the formation of metabolites having pharmacological, toxicological or physiological effects. For a few years, the role of the P450 cytochromes in the metabolism of the acid arachidonic has been well described. Among the metabolites produced at the time of this biotransformation, the epoxyeicosatrinoïc acids (EETs) and the hydroxyeicosatetraenoïc acids (HETEs) occupy an important place in the regulation of vascular tone. Thus EETs have vasodilatator properties while HETEs have maily vasoconstrictor properties. During this work, we studied the expression of various P450 cytochromes in the human saphenous veins and we characterized the expression profile of these enzymes in various cellular types contained in the vascular walls. We showed that the expression of the majority of the cytochromes P450, in particular CYP1B, CYP2C, CYP2E1, CYP2J2 and CYP3A, was increased in the samples of human varicose veins. We have studied the regulation of various cytochromes P450, namely CYP2C, occupying an important place in the regulation of vascular homeostasis, by some statins in human endothelial cells (EV304) and human hepatoblastoma cell line (HepG2). The statins are molecules used in the treatment of the hypercholesterolemia, presenting pleiotropic effects, in particular on the vascular function. We observed that atorvastatin was the molecule having the most effect on the expression of the cytochromes P450 2C8, 2C9, 2J2, 3A5 and 3A7. Indeed, this molecule decreases the expression of the various cytochromes P450in ECV304 cells whereas it increases their expression in the HepG2 cells. The statines also influence the expression of two types of nuclear receptor implied in the regulation of the cytochromes P450. Thus, fluvastatin, increases the expression of the nuclear receptors CAR and PXR. Lastly, we studied the effect of the polymorphism of a cytochrome P450 of the 2C family on the blood pressure and the inflammatory markers of cardiovascular pathologies. We observed that the values of blood pressures did not vary according to the polymorphism of CYP2C19. On the other hand, the plasma levels of interleukine-6 are higher at the carriers of the allele CYP2C19*2. In the same way, the plasma concentrations of the lipidic parameters such as triglycerides are higher at the same subjects. Thus, a modification of the expression of the cytochromes P450can play a part in varicose pathology and vascular pathology with inflammatory component. This expression can be modulated by the statins. Lastly, polymorphism CYP2C19*2 is correlated with the inflammatory component of vascular pathologies probably via the metabolites of the acid arachidonic. These results then raise the question of the modulation of the production of the vaso-active molecules resulting from the arachidonic acid in vascular pathologies and from possible treatments by the statins or by inhibitors of P450 cytochromes., Les cytochromes P450 (CYP) sont des enzymes dont le rôle principalement connu est la détoxification. Cependant, leur activité peut conduire à la formation de métabolites ayant des effets pharmacologiques, toxicologiques ou physiologiques. Depuis quelques années, le rôle des cytochromes P450 dans le métabolisme de l'acide arachidonique est bien décrit. Parmi les métabolites produits lors de cette biotransformation, les acides epoxyeicosatriènoïques (les EETs) et les acides hydroxyeicosatetraènoïques (les HETEs) occupent une place importante dans la régulation du tonus vasculaire. Ainsi les EETs ont des propriétés vasodilatatrices tandis que les HETEs ont des propriétés surtout vasoconstrictrices. Au cours de ce travail, nous avons étudié l'expression de certains cytochromes P450 dans les veines saphènes humaines et nous avons caractérisé le profil d'expression de ces enzymes dans différents types cellulaires contenus dans les parois vasculaires. Nous avons montré que l'expression de la plupart des cytochromes P450, notamment CYP1B, CYP2C, CYP2E1, CYP2J2 et CYP3A, était augmentée dans les échantillons de veines variqueuses humaines. Nous avons ensuité étudié dans une lignée de cellules endothéliales humaines (EV304) et une lignée d'hépatomes d'origine humaine (HepG2), la régulation par quelques statines de certains cytochromes P450, dont les CYP2C, occupant une place importante dans le régulation de l'homéostasie vasculaire. Les statines sont des molécules utilisées dans le traitement de l'hypercholestérolémie, présentant des effets pleïotropiques, notamment sur l'état vasculaire. Nous avons observé que l'atorvastatine était la molécule ayant le plus d'effet sur l'expression des cytochromes P450 2C8, 2C9, 2J2, 3A5 et 3A7. En effet, cette molécule diminue l'expression des différents cytochromes P450 dans les cellules ECV304 alors qu'elle augmente leur expression dans les cellules HepG2. les statines influencent également l'expression de deux types de récepteurs nucléaires impliqués dans la régulation des cytochromes P450. Ainsi, la fluvastatine, augmente l'expression des récepteurs nucléaires CAR et PXR. Enfin, nous avons étudié l'effet du polymorphisme d'un cytochrome P450 de la famille 2C sur la pression sanguine et sur les marqueurs inflammatoires des pathologies cardiovasculaires. Nous avons observé que les valeurs de pressions sanguines ne variaient pas en fonction du polymorphisme de CYP2C19. En revanche, les taux plasmatiques d'interleukine-6 sont plus élevés chez les porteurs de l'allèle muté CYP2C19*2. De la même façon, les concentrations plasmatiques des paramètres lipidiques tels que les triglycerides sont plus élevés chez les mêmes sujets. Ainsi, une modification de l'expression des cytochromes P450 peut jouer un rôle dans la pathologie variqueuse et dans la pathologie vasculaire à composante inflammatoire. Cette expression peut être modulée par les statines. Enfin, le polymorphisme CYP2C19*2 est corrélé avec la composante inflammatoire des pathologies vasculaires probablement par l'intermédiaire des métabolites de l'acide arachidonique. Ces résultats posent alors la question de la modulation de la production des molécules vaso-actives issues de l'acide arachidonique dans les pathologies vasculaires et d'éventuels traitements par les molécules inhibitrices de l'HMGCoA réductase ou par des inhibiteurs de cytochromes P450.
Published: 2004

42. Smoking, genetic polymorphisms of glutathione S-transferases and biological indices of inflammation and cellular adhesion in the STANISLAS study

Author: Mohammed Habdous, Bernard Herbeth, Nadia Haddy, Anne Ponthieux, Bolt, Hermann M., Gérard Siest, Ricarda Thier, Daniel Lambert, Sophie Visvikis-Siest, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), and Haddy, Nadia
Subjects: 0303 health sciences, molecule, 030204 cardiovascular system & hematology, smoking, adhesion molecule, 3. Good health, glutathione S-transferase polymorphism, 03 medical and health sciences, adhesion, 0302 clinical medicine, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, inflammation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030304 developmental biology
Abstract: A recent clinical study has focused on: 1- the interaction between genetic variants of glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) and smoking on the risk of cardiovascular diseases, 2- the potential capacity of GSTM1 and T1 genotypes in modifying the effect of smoking on inflammation and endothelial function. In this study, we investigated whether carriage of these 2 polymorphisms altered the smoking impact on biological indices of inflammation and cellular adhesion. White blood cell count (WBC), albumin, C-reactive protein (CRP), interleukine-6 (IL-6), tumor necrosis factor-alpha (TNF-a), L-selectin, E-selectin, P-selectin and intracellular adhesion molecule-1 (ICAM-1) were measured in 189 non-smokers and 76 smokers (aged 20-55 years) genotyped for the GSTM1 and T1 polymorphisms. Accounting for age and sex, smokers lacking GSTM1 had a higher WBC count, CRP and ICAM-1 levels as compared to the other groups; interaction term between smoking and genotype being significant (p=0.05). Conversely, non-smokers lacking GSTM1 had a higher levels of TNF-a; the test for interaction being significant (p=0.05). No significant interaction was found between smoking and GSTT1 genotypes, considering the 9 biological indices. However, significantly lower levels of IL-6 were noticed for non-smokers with GSTT1-0 null allele (p=0.05). Our study confirms previous results showing that GSTM1 polymorphism could modulate the interrelationships between smoking and biological markers of inflammation and endothelial function., EXCLI Journal ; Vol. 3, 2004
Published: 2004

43. Profiling of aortic smooth muscle cell gene expression in response to chronic inhibition of nitric oxide synthase in rats

Author: Jean-Baptiste Michel, Ségolène Raoux, Liliane Louedec, Mounsif Haloui, Morgan Dupuis, Florent Soubrier, Isabelle Brocheriou, Sophie Nadaud, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Transcription, Genetic, [SDV]Life Sciences [q-bio], Cell, Myocytes, Smooth Muscle, Muscle, Smooth, Vascular, Nitric oxide, chemistry.chemical_compound, Transcription (biology), Physiology (medical), Internal medicine, medicine.artery, Gene expression, medicine, Animals, Aorta, Abdominal, Enzyme Inhibitors, Gene, Oligonucleotide Array Sequence Analysis, Aorta, biology, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Molecular biology, Rats, Inbred F344, Extracellular Matrix, Rats, Nitric oxide synthase, Endocrinology, medicine.anatomical_structure, NG-Nitroarginine Methyl Ester, chemistry, Gene Expression Regulation, Muscle Tonus, biology.protein, DNA microarray, Nitric Oxide Synthase, Cardiology and Cardiovascular Medicine, business, Tunica Media, Cell Division, Signal Transduction
Abstract: Background— Chronic inhibition of nitric oxide (NO) synthesis by N ω -nitro- l -arginine methyl ester (L-NAME) induces hypertension associated with remodeling of the arterial wall. In this study, we aimed at identifying genes and pathways involved in this process in aortic smooth muscle cells from Fischer 344 rats, which exhibit an accelerated hypertension after administration of L-NAME. Methods and Results— We studied the transcriptional profile of aortic media after 15 days (moderate hypertension) and 30 days (accelerated hypertension) of L-NAME administration (50 mg · kg −1 · d −1 ) by using rat Affymetrix Genechips, and we present a large-scale validation of the DNA chip results by real-time reverse transcription–polymerase chain reaction (RT-PCR). We observed, in aortic media, a progressive increase in the number of modulated genes during L-NAME administration, with 53 genes significantly modulated after 15 days and 147 genes after 30 days. These expression changes were confirmed at 87% by RT-PCR. We found 28 known genes regulated at both 15 and 30 days (96% confirmation by RT-PCR). The functional classification of the regulated genes highlights 3 major biological pathways modulated in aortic media during L-NAME administration: genes regulating cell proliferation, genes involved in the extracellular matrix remodeling, and genes of the NO/cGMP signaling pathway. Conclusions— As a consequence of the genomic approach, we observed a large increase in modulation of gene expression along the evolution of the model and the progressive implication of compensatory mechanisms, making expression profile analysis more complex.
Published: 2004
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44. Incubation of rat aortic rings produces a specific reduction in agonist-evoked contraction: effect of age of donor

Author: Angela C. Resende, Isabelle Lartaud, Sophie Nadaud, Christine Capdeville-Atkinson, Denyse Bagrel, Sebastien Faure, Aurore Tabellion, Jeffrey Atkinson, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Contraction (grammar), Pyrrolidines, Time Factors, [SDV]Life Sciences [q-bio], Glutathione reductase, Nitric Oxide Synthase Type II, Aorta, Thoracic, Muscle, Smooth, Vascular, chemistry.chemical_compound, Norepinephrine, General Pharmacology, Toxicology and Pharmaceutics, Incubation, Chemistry, Reverse Transcriptase Polymerase Chain Reaction, Age Factors, General Medicine, Catalase, Glutathione, Propranolol, Isoenzymes, Biochemistry, Spectrophotometry, medicine.symptom, medicine.drug, Muscle Contraction, medicine.medical_specialty, Serotonin, General Biochemistry, Genetics and Molecular Biology, Contractility, Thiocarbamates, Internal medicine, medicine.artery, medicine, Animals, RNA, Messenger, Rats, Wistar, DNA Primers, Aorta, Analysis of Variance, Culture Media, Rats, Endocrinology, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Potassium, Nitric Oxide Synthase, Vasoconstriction
Abstract: We studied the effect of age on the response of aortic rings to injury produced by three days' incubation, and the mechanism of this response. Five-mm rings of the thoracic aorta isolated from Wistar rats were incubated or not in culture medium. Isometric contraction evoked by agonists (norepinephrine or serotonin) or high [K(+)](e) was determined in the presence and absence of endothelium. Experiments were repeated in the presence of propranolol (0.3 microM), polymixin B (36 microM), pyrrolidine dithiocarbamate (50 microM) or glutathione (3 mM). Inductible NO-synthase and cyclo-oxygenase-2 mRNA were determined by real-time PCR, and glutathione-related enzymes and catalase activity by spectrophotometry. Incubation reduced the isometric contraction evoked by agonists but not by high [K(+)](e). The reduction in agonist-evoked contraction was greater in rings from adult (norepinephrine Emax-80%) than in young (-40%) rats. The removal of the endothelium had no effect. The reduction in norepinephrine-evoked contraction was not due to endotoxin contamination, beta-adrenoceptor-mediated dilation or any change in ring structure (no fibrosis or edema). Inductible NO-synthase (but not cyclo-oxygenase-2) mRNA increased on incubation. N(G)-nitro-L-arginine methyl ester partially restored contractility in rings from adult animals, further addition of an anti-oxidant restored norepinephrine-evoked contraction. Catalase fell with age and glutathione reductase increased upon incubation in rings from young donors only. In conclusion, incubation of the aorta produces a specific reduction in agonist-evoked contraction that involves induction of smooth muscle cell oxidative stress and iNOS. The reaction is greater in rings from older animals.
Published: 2003
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45. IL-6, TNF-alpha and atherosclerosis risk indicators in a healthy family population: the STANISLAS cohort

Author: Daniel Lambert, Nadia Haddy, Gérard Siest, Suzanne Droesch, Catherine Sass, Sophie Visvikis, Mohamed Zaiou, Anne Ponthieux, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Arteriosclerosis, MESH: Apolipoprotein A-I, Cohort Studies, MESH: Cholesterol, Risk Factors, MESH: Risk Factors, MESH: Aging, MESH: Cohort Studies, MESH: Aged, education.field_of_study, MESH: Middle Aged, biology, Haptoglobin, Intercellular Adhesion Molecule-1, MESH: Apolipoproteins E, Lipids, C-Reactive Protein, Cohort, Female, France, Inflammation Mediators, MESH: Cholesterol, HDL, Cardiology and Cardiovascular Medicine, Cohort study, MESH: Sex Characteristics, Adult, MESH: Triglycerides, medicine.medical_specialty, MESH: Smoking, Offspring, Population, MESH: Inflammation Mediators, Proinflammatory cytokine, MESH: Body Mass Index, Internal medicine, MESH: Polymorphism, Genetic, MESH: C-Reactive Protein, medicine, Humans, Risk factor, education, Family Health, MESH: Humans, Apolipoprotein A-I, Interleukin-6, Tumor Necrosis Factor-alpha, business.industry, MESH: Intercellular Adhesion Molecule-1, Cholesterol, HDL, C-reactive protein, MESH: Contraceptive Agents, MESH: Selectins, MESH: Adult, MESH: Interleukin-6, MESH: Lipids, MESH: Male, MESH: France, Endocrinology, MESH: Arteriosclerosis, MESH: Tumor Necrosis Factor-alpha, Selectins, biology.protein, MESH: Family Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Europe, business, MESH: Female
Abstract: There are no satisfactory data on circulating concentrations of inflammatory cytokines and their potential relationship with traditional and nontraditional atherosclerosis risk factors in a large healthy young population. The present study was conducted to examine, in 179 healthy families selected from the STANISLAS cohort, the association between interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), orosomucoid, haptoglobin, cell-adhesion molecules (ICAM-1, E-, L- and P-selectin) and lipid parameter concentrations. Age, BMI, white blood cells and tobacco consumption contributed to the variation of IL-6 concentrations. Age and tobacco contributed also to TNF-alpha variation. Taking into account potential covariates, we showed strong positive correlation between IL-6 and both inflammatory markers TNF-alpha and CRP in parents and in offspring (P
Published: 2003
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46. Biological determinants of serum ICAM-1, E-selectin, P-selectin and L-selectin levels in healthy subjects: the Stanislas study

Author: Daniel Lambert, Anne Ponthieux, Suzanne Droesch, Sophie Visvikis, Nadia Haddy, Bernard Herbeth, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Blood Glucose, Male, P-selectin, MESH: Apolipoprotein A-I, 030204 cardiovascular system & hematology, MESH: Regression Analysis, Body Mass Index, Leukocyte Count, 0302 clinical medicine, MESH: Alkaline Phosphatase, MESH: Child, Medicine, MESH: L-Selectin, Homeostasis, L-Selectin, Child, 2. Zero hunger, 0303 health sciences, ICAM-1, MESH: Middle Aged, biology, Smoking, Age Factors, MESH: Enzyme-Linked Immunosorbent Assay, Middle Aged, Intercellular Adhesion Molecule-1, 3. Good health, P-Selectin, C-Reactive Protein, MESH: Homeostasis, Child, Preschool, MESH: P-Selectin, Alkaline phosphatase, Regression Analysis, L-selectin, Female, Cardiology and Cardiovascular Medicine, MESH: Contraceptives, Oral, E-Selectin, Adult, medicine.medical_specialty, MESH: E-Selectin, MESH: Smoking, Adolescent, Aspartate transaminase, Enzyme-Linked Immunosorbent Assay, MESH: Erythrocyte Count, MESH: Body Mass Index, 03 medical and health sciences, MESH: Aspartate Aminotransferases, Sex Factors, MESH: Sex Factors, Internal medicine, E-selectin, MESH: C-Reactive Protein, Humans, MESH: Platelet Count, Aspartate Aminotransferases, 030304 developmental biology, MESH: Adolescent, MESH: Age Factors, MESH: Humans, Apolipoprotein A-I, business.industry, Platelet Count, Tumor Necrosis Factor-alpha, MESH: Intercellular Adhesion Molecule-1, C-reactive protein, MESH: Child, Preschool, MESH: Adult, Alkaline Phosphatase, MESH: Male, Endocrinology, MESH: Leukocyte Count, MESH: Tumor Necrosis Factor-alpha, Immunology, biology.protein, MESH: Blood Glucose, Erythrocyte Count, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Body mass index, MESH: Female, Contraceptives, Oral
Abstract: Background: Circulating levels of adhesion molecules increase in various inflammation-related diseases, such as atherosclerosis. However, data about factors influencing their concentrations in physiological conditions are scarce. Methods: We have studied the determinants of serum levels of intercellular adhesion molecule-1 (ICAM-1), E-selectin, P-selectin and L-selectin in a sample of healthy individuals: 303 children (4–17 years) and 493 adults (18–55 years). The concentrations of these molecules have been measured by enzyme-linked immunosorbant assay. Results: As far as the children are concerned, a decrease in the levels of ICAM-1, E-selectin, P-selectin and L-selectin has been noticed for both boys and girls aged 4–17 years, without any difference between genders. For the adults, no age-related variation has been found for the ICAM-1, E-selectin and P-selectin levels, while the L-selectin level decreased until 55 years old. In the adult group, no sex-related difference in the concentrations of ICAM-1, E-selectin and L-selectin has been seen. As to the P-selectin level, men had significantly higher levels than women. Multiple regression analysis showed that smoking, homeostasis model assessment (HOMA) index, aspartate aminotransferase (AST), alkaline phosphatase (ALP) and C-reactive protein (CRP) were significant positive determinants of the ICAM-1 concentration, whereas age and apo AI were negative ones. The E-selectin level was positively associated with body mass index (BMI), leukocyte, platelet and erythrocyte counts, glucose, ALP and tumor necrosis factor-alpha (TNF-α), and negatively related to the use of oral contraceptive (OC). Positive determinants of the P-selectin concentration were leukocyte, platelet and erythrocyte counts, whereas sex, the use of oral contraceptive, glucose and TNF-α were negative determinants of P-selectin. Only two determinants have been noticed for the concentration of serum L-selectin: age, which was negatively correlated, and leukocyte count, which was positively associated. Conclusion: Our study contributes to the understanding of the regulation of adhesion molecules in physiological conditions.
Published: 2003
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47. Family studies: their role in the evaluation of genetic cardiovascular risk factors

Author: Sophie Visvikis, Marianne Mansour-Chemaly, Nadia Haddy, Gérard Siest, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Candidate gene, Pathology, medicine.medical_specialty, Clinical Biochemistry, MESH: Environmental Exposure, Disease, 030204 cardiovascular system & hematology, Bioinformatics, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, Risk Factors, MESH: Risk Factors, Epidemiology, medicine, Genetic predisposition, Humans, Family, Genetic Predisposition to Disease, 030212 general & internal medicine, Risk factor, MESH: Cohort Studies, MESH: Family, MESH: Humans, business.industry, Biochemistry (medical), MESH: Genetic Predisposition to Disease, MESH: Cardiovascular Diseases, Environmental Exposure, General Medicine, 3. Good health, Cardiovascular Diseases, Cohort, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Cohort study
Abstract: Early epidemiological studies showed that genetic factors contribute to the risk of cardiovascular disease. Genetic epidemiological studies based upon families can be used to investigate familial trait aggregation, to localize genes implicated in cardiovascular diseases in the human genome, and to establish the role of environmental factors. Family studies can be also used to identify the physiological role of candidate genes for cardiovascular diseases, and to characterize shared environmental risk factors and their impact on the expression of genetic predisposition. The present paper reviews the existing family studies with special emphasis on those which have studied healthy populations in relation to cardiovascular disease such as the Framingham Heart Study, the National Heart, Lung, and Blood Institute Family Heart Study, and the STANISLAS cohort.
Published: 2002

48. Characterization of an Upstream Enhancer Region in the Promoter of the Human Endothelial Nitric-oxide Synthase Gene

Author: Florent Soubrier, Yves Laumonnier, Monique Agrapart, Sophie Nadaud, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Nitric Oxide Synthase Type III, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Enhancer RNAs, Biology, Biochemistry, Deoxyribonuclease I, Humans, Binding site, Promoter Regions, Genetic, Enhancer, Molecular Biology, Transcription factor, Cells, Cultured, Binding Sites, Base Sequence, Activator (genetics), Cell Biology, Molecular biology, Upstream Enhancer, Enhancer Elements, Genetic, Nucleoproteins, Nitric Oxide Synthase, Transcription Factors
Abstract: The endothelial nitric-oxide synthase gene is constitutively expressed in endothelial cells. Several transcriptionally active regulatory elements have been identified in the proximal promoter, including a GATA-2 and an Sp-1 binding site. Because they cannot account for the constitutive expression of endothelial nitric-oxide synthase gene in a restricted number of cells, we have searched for other cell-specific regulatory elements. By DNase I hypersensitivity mapping and deletion studies we have identified a 269-base pair activator element located 4.9 kilobases upstream from the transcription start site that acts as an enhancer. DNase I footprinting and linker-scanning experiments showed that several regions within the 269-base pair enhancer are important for transcription factor binding and for full enhancer activity. The endothelial specificity of this activation seems partly due to interaction between this enhancer in its native configuration and the promoter in endothelial cells. EMSA experiments suggested the implication of MZF-like, AP-2, Sp-1-related, and Ets-related factors. Among Ets factors, Erg was the only one able to bind to cognate sites in the enhancer, as found by EMSA and supershift experiments, and to activate the transcriptional activity of the enhancer in cotransfection experiments. Therefore, multiple protein complexes involving Erg, other Ets-related factors, AP-2, Sp-1-related factor, and MZF-like factors are important for the function of this enhancer in endothelial cells.
Published: 2000
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49. Effects of chronic and acute aminoguanidine treatment on tail artery vasomotion in ageing rats

Author: A, Tabernero, S, Nadaud, B, Corman, J, Atkinson, C, Capdeville-Atkinson, Laboratoire de neurobiologie et pharmacologie cardiovasculaire (LNPCV), Université de Strasbourg (UNISTRA), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Nadaud, Sophie
Subjects: Male, Tail, Dose-Response Relationship, Drug, [SDV]Life Sciences [q-bio], Age Factors, Nitric Oxide Synthase Type II, Arteries, Guanidines, Rats, [SDV] Life Sciences [q-bio], Norepinephrine, NG-Nitroarginine Methyl Ester, Vasoconstriction, Papers, Animals, Vasoconstrictor Agents, Calcium, Endothelium, Vascular, RNA, Messenger, Enzyme Inhibitors, Nitric Oxide Synthase
Abstract: International audience; 1. This study was designed to evaluate the effects of aminoguanidine, a selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), on the reactivity and intracellular calcium ([Ca(2+)](i)) mobilization induced by noradrenaline in the perfused tail artery from aged WAG/Rij rats. Global mean internal diameter was 350+/-15 microns and wall thickness 161+/-3 microns. The influence of the endothelium on these responses was also analysed. The intracellular dye fura-2 for [Ca(2+)](i) measurements was used. 2. Noradrenaline-induced vasoconstriction decreased progressively from 3 to 20 and 30 months. Removal of the endothelium attenuated vasoconstriction in 20 and 30 month-old rats (P
Published: 2000
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50. Polymorphisms in the genes encoding platelet-derived growth factor A and alpha receptor.

Author: Herrmann SM, Ricard S, Nicaud V, Brand E, Behague I, Blanc H, Ruidavets JB, Evans A, Arveiler D, Luc G, Poirier O, and Cambien F
Subjects: Adult, Case-Control Studies, Gene Frequency, Genetic Predisposition to Disease, Haplotypes genetics, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single-Stranded Conformational, Sequence Analysis, DNA, Myocardial Infarction genetics, Platelet-Derived Growth Factor genetics, Polymorphism, Genetic, Receptor, Platelet-Derived Growth Factor alpha genetics
Abstract: Platelet-derived growth factors (PDGFs) may play an important role in the development of atherosclerosis acting as chemoattractants and mitogens for vascular smooth muscle cells and macrophages. Three dimeric forms of PDGF (AA, AB, BB) have different activities due to distinct binding properties mediated by two types of PDGF receptors (Ralpha, Rbeta). To investigate the possible contribution of molecular variants in the human PDGF-A and PDGF-Ralpha genes to coronary heart disease we screened these genes for polymorphisms by polymerase chain reaction/single-strand conformation polymorphism analysis. A total of 600 men with myocardial infarction and 717 age-matched male controls from four populations in Northern Ireland and France (the ECTIM Study) were gneotyped for newly identified polymorphisms in the genes encoding PDGF-A (C-26IN3T, H69H, C+12IN5T) and PDGF-Ralpha [-1630 I/D (+/-AACTT), A-1506G, C-1390G, G-956A, C-908A, G-793T, +69 I/D (+/-GA)] using allele-specific oligonucleotides. All PDGF-Ralpha polymorphisms, except C-908A, involving a nucleotide change in a common consensus site for GCF and SP-1 transcription factors, were in nearly complete association, generating two major haplotypes. The PDGF-A and PDGF-Ralpha polymorphisms provided a heterozygosity of 0.69 and 0.40, respectively. Genotype and allele frequencies of the PDGF-A and PDGF-Ralpha polymorphisms did not differ between patients with myocardial infarction and controls in either country. None of the polymorphisms investigated was associated with blood pressure, coronary artery stenosis, or any biochemical parameter available in the ECTIM Study.
Published: 2000
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