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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. 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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4. 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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5. 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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6. 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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7. 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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8. 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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9. 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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10. 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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11. 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

12. 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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13. 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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14. 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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15. 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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16. 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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17. 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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18. 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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19. 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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20. 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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21. 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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22. 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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23. 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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24. 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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25. 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

26. 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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27. The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe

Author: Dirk De Bacquer, Mickaël Maurice, Maria do Carmo Martins, Gérard Siest, Susanna Sans, Sophia Visvikis, Marianne Mansour Chemaly, Alun Evans, Christian Ehnholm, Nadia Haddy, Guy De Backer, 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 Public Health, and State University of Ghent
Subjects: Male, Apolipoprotein E, Aging, 030204 cardiovascular system & hematology, Body Mass Index, Doenças Cardio e Cérebro-vasculares, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, MESH: Cholesterol, Polymorphism (computer science), ApoEurope, Genotype, MESH: Aging, Genetics (clinical), Genetics, MESH: Aged, Sex Characteristics, 0303 health sciences, MESH: Middle Aged, ApoE Concentration, Smoking, Middle Aged, MESH: Apolipoproteins E, 3. Good health, Europe, Cholesterol, Female, lipids (amino acids, peptides, and proteins), MESH: Sex Characteristics, Adult, MESH: Triglycerides, medicine.medical_specialty, MESH: Smoking, Biology, Inter-individual Lipid Levels Variation, MESH: Body Mass Index, 03 medical and health sciences, Apolipoproteins E, Contraceptive Agents, Internal medicine, Plasma lipids, MESH: Polymorphism, Genetic, medicine, Humans, Allele frequency, Triglycerides, Aged, 030304 developmental biology, Polymorphism, Genetic, MESH: Humans, MESH: Contraceptive Agents, Lipid metabolism, MESH: Adult, medicine.disease, MESH: Male, Endocrinology, chemistry, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Europe, ApoE Polymorphism, MESH: Female, Cardiovascular Risk
Abstract: The ApoEurope group, collaborating centres, and their associated investigators: Portugal: Unidade de Química Clínica, Instituto Nacional de Saúde, Lisboa: Maria do Carmo Martins, Maria Odete Rodrigues, Maria Isabel Albergaria, Maria Liseta Alpendre Interindividual variation in the concentration of plasma lipids which are associated with coronary artery disease (CAD) risk is determined by a combination of genetic and environmental factors. This study investigates the effects of apoE genotype and plasma concentration on cholesterol and triglycerides (TG) levels in subjects from five countries: Finland, France, Northern Ireland, Portugal, and Spain. Age and sex significantly influenced serum cholesterol, TG and apoE concentrations. The age effect differs in males and females. The allele frequencies of the apoE gene, one of the most widely studied CAD susceptibility genes, were determined: the epsilon2 allele frequency and the apoE concentration showed a north-south increasing gradient while the epsilon4 allele frequency showed the reverse. ApoE plays an important role in lipid metabolism. Total cholesterol and TG concentrations were significantly dependent on apoE genotype in both sexes. These differences in lipids between genotypes were more pronounced when plasma apoE concentrations were taken into account.
Published: 2002
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28. 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

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28 results on '"Génétique épidémiologique et moléculaire des pathologies cardiovasculaires"'

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

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

3. Impact of coronary artery disease in patients undergoing transcatheter aortic valve replacement: Insights from the FRANCE-2 registry

4. The Genetic Landscape of Renal Complications in Type 1 Diabetes

5. Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study

6. Platelet protease nexin-1, a serpin that strongly influences fibrinolysis and thrombolysis.: Platelet Protease Nexin-1 Is Antithrombolytic

7. Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling

8. Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft

9. Pharmacogenomics and antihypertensive drugs: a path toward personalized medicine

10. Fetal and maternalMTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts

11. In Vitro fertilization failure of normozoospermic men: search for a lack of testicular isozyme of angiotensin-converting enzyme

12. Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage

13. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1

14. Molecular and functional characterization of polymorphisms in the secreted phospholipase A2 group X gene: relevance to coronary artery disease

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

16. APOE genotype, ethnicity, and the risk of cerebral hemorrhage

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

18. Fetal and maternal CYP2E1 genotypes and the risk of nonsyndromic oral clefts

19. Genetic variations at the endocannabinoid type 1 receptor gene (CNR1) are associated with obesity phenotypes in men

20. Atherogenic properties of LDL particles modified by human group X secreted phospholipase A2 on human endothelial cell function

21. The proinflammatory mediator Platelet Activating Factor is an effective substrate for human group X secreted phospholipase A2

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

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

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

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

26. Biological determinants of serum ICAM-1, E-selectin, P-selectin and L-selectin levels in healthy subjects: the Stanislas study

27. The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe

28. Family studies: their role in the evaluation of genetic cardiovascular risk factors

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