Genetic association analyses highlight biological pathways underlying mitral valve prolapse.

Autor: Dina C; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France., Bouatia-Naji N; INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.; Paris Descartes University, Paris Sorbonne Cité, Paris, France., Tucker N; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA., Delling FN; Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.; Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Toomer K; Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA., Durst R; Department of Cardiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel., Perrocheau M; INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.; Paris Descartes University, Paris Sorbonne Cité, Paris, France., Fernandez-Friera L; Hospital Universitario Montepríncipe, Universidad Centro de Estudios Universitarios (CEU) San Pablo, Madrid, Spain.; Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain., Solis J; Hospital Universitario Montepríncipe, Universidad Centro de Estudios Universitarios (CEU) San Pablo, Madrid, Spain.; Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain., Le Tourneau T; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France., Chen MH; Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.; Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA., Probst V; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France., Bosse Y; Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada., Pibarot P; Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada., Zelenika D; Centre National de Génotypage, Evry, France., Lathrop M; Centre National de Génotypage, Evry, France.; Génome Québec, Montreal, Quebec, Canada., Hercberg S; Paris Descartes University, Paris Sorbonne Cité, Paris, France.; Paris 13 University, Sorbonne Paris Cité, Bobigny, France.; INSERM U1153, Institut National de Recherche en Agronomie (INRA) U1125, Nutritional Epidemiology Research Unit, Epidemiology and Biostatistics Center, Bobigny, France.; Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Public Health, Avicenne Hospital, Bobigny, France.; Paris Diderot University, Paris, France., Roussel R; Paris Diderot University, Paris, France.; INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.; AP-HP, Department of Endocrinology, Diabetes and Nutrition, Fibrosis, Inflammation, Remodeling in Cardiovascular, Respiratory and Renal Diseases (FIRE) Department Hospital University, Bichat Hospital, Paris, France., Benjamin EJ; Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.; Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Bonnet F; INSERM, Clinical Investigation Centre (CIC) 0203, University Hospital of Pontchaillou, Rennes, France.; Department of Endocrinology, University Hospital, Rennes, France., Lo SH; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, California, USA., Dolmatova E; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA., Simonet F; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France., Lecointe S; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France., Kyndt F; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France., Redon R; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France., Le Marec H; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France., Froguel P; CNRS UMR 8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille, France.; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK., Ellinor PT; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA., Vasan RS; Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA., Bruneval P; INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.; Paris Descartes University, Paris Sorbonne Cité, Paris, France.; AP-HP, Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France., Markwald RR; Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA., Norris RA; Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA., Milan DJ; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA., Slaugenhaupt SA; Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Levine RA; Cardiac Ultrasound Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Schott JJ; INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.; Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France., Hagege AA; INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.; AP-HP, Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, France., Jeunemaitre X; INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.; Paris Descartes University, Paris Sorbonne Cité, Paris, France.; AP-HP, Department of Genetics, Hôpital Européen Georges Pompidou, Paris, France.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2015 Oct; Vol. 47 (10), pp. 1206-11. Date of Electronic Publication: 2015 Aug 24.
DOI: 10.1038/ng.3383
Abstrakt: Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1(-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.
Databáze: MEDLINE