Format

Send to

Choose Destination
Nat Genet. 2015 Oct;47(10):1206-11. doi: 10.1038/ng.3383. Epub 2015 Aug 24.

Genetic association analyses highlight biological pathways underlying mitral valve prolapse.

Author information

1
INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.
2
Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
3
INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.
4
Paris Descartes University, Paris Sorbonne Cité, Paris, France.
5
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
6
Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.
7
Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
8
Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
9
Department of Cardiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
10
Hospital Universitario Montepríncipe, Universidad Centro de Estudios Universitarios (CEU) San Pablo, Madrid, Spain.
11
Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain.
12
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
13
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.
14
Centre National de Génotypage, Evry, France.
15
Génome Québec, Montreal, Quebec, Canada.
16
Paris 13 University, Sorbonne Paris Cité, Bobigny, France.
17
INSERM U1153, Institut National de Recherche en Agronomie (INRA) U1125, Nutritional Epidemiology Research Unit, Epidemiology and Biostatistics Center, Bobigny, France.
18
Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Public Health, Avicenne Hospital, Bobigny, France.
19
Paris Diderot University, Paris, France.
20
INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
21
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.
22
INSERM, Clinical Investigation Centre (CIC) 0203, University Hospital of Pontchaillou, Rennes, France.
23
Department of Endocrinology, University Hospital, Rennes, France.
24
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, California, USA.
25
CNRS UMR 8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille, France.
26
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
27
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
28
AP-HP, Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.
29
Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
30
Cardiac Ultrasound Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
31
AP-HP, Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, France.
32
AP-HP, Department of Genetics, Hôpital Européen Georges Pompidou, Paris, France.

Abstract

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.

PMID:
26301497
PMCID:
PMC4773907
DOI:
10.1038/ng.3383
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center