Genetic association analyses highlight biological pathways underlying mitral valve prolapse

Christian Dina 1, 2 Nabila Bouatia-Naji 3 Nathan Tucker Francesca N. Delling Katelynn Toomer Ronen Durst Maelle Perrocheau 3 Leticia Fernandez-Friera Jorge Solis Thierry Le Tourneau 1 Ming-Huei Chen Vincent Probst 1 Yohan Bosse Philippe Pibarot 4 Diana Zelenika 5 Mark Lathrop 5 Serge Hercberg 6, 7 Ronan Roussel 8 Emelia J. Benjamin Fabrice Bonnet 9 Su Hao Lo Elena Dolmatova Floriane Simonet 1 Simon Lecointe 1 Florence Kyndt 1 Richard Redon 1 Hervé Le Marec 1 Philippe Froguel 10, 11 Patrick T. Ellinor Ramachandran S. Vasan Patrick Bruneval 12, 13 Roger R. Markwald Russell A. Norris David J. Milan Susan A. Slaugenhaupt Robert A. Levine Jean-Jacques Schott 1 Albert A. Hagege Xavier Jeunemaitre 3, 14, 13
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
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Christian Dina, Nabila Bouatia-Naji, Nathan Tucker, Francesca N. Delling, Katelynn Toomer, et al.. Genetic association analyses highlight biological pathways underlying mitral valve prolapse. Nature Genetics, Nature Publishing Group, 2015, 47 (10), pp.1206-1211. ⟨10.1038/ng.3383⟩. ⟨hal-01191656⟩

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