Genetic association analyses highlight biological pathways underlying mitral valve prolapsed

Christian Dina, Nabila Bouatia-Naji, Nathan Tucker, Francesca N. Delling, Katelynn Toomer, Ronen Durst, Maelle Perrocheau, Leticia Fernandez-Friera, Jorge Solis, Thierry Le Tourneau, Ming Huei Chen, Vincent Probst, Yohan Bosse, Philippe Pibarot, Diana Zelenika, Mark Lathrop, Serge Hercberg, Ronan Roussel, Emelia J. Benjamin, Fabrice BonnetSu Hao Lo, Elena Dolmatova, Floriane Simonet, Simon Lecointe, Florence Kyndt, Richard Redon, Hervé Le Marec, Philippe Froguel, Patrick T. Ellinor, Ramachandran S. Vasan, Patrick Bruneval, Roger R. Markwald, Russell A. Norris, David J. Milan, Susan A. Slaugenhaupt, Robert A. Levine, Jean Jacques Schott, Albert A. Hagege, Xavier Jeunemaitre

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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 â '/â ' 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.

Original languageEnglish (US)
Pages (from-to)1206-1211
Number of pages6
JournalNature Genetics
Volume47
Issue number10
DOIs
StatePublished - Sep 29 2015

ASJC Scopus subject areas

  • Genetics

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