Genetic association analyses highlight biological pathway underlying mitral valve prolapse.

Nat Genet. 2015 Oct

Dina C*, Bouatia-Naji N*, Tucker N, Delling FN, Toomer K, Durst R, Perrocheau M, Fernandez-Friera L, Solis J; PROMESA investigators, Le Tourneau T, Chen MH, Probst V, Bosse Y, Pibarot P, Zelenika D, Lathrop M, Hercberg S, Roussel R, Benjamin EJ, Bonnet F, Lo SH, Dolmatova E, Simonet F, Lecointe S, Kyndt F, Redon R, Le Marec H, Froguel P, Ellinor PT, Vasan RS, Bruneval P, Markwald RR, Norris RA, Milan DJ, Slaugenhaupt SA, Levine RA, Schott JJ, Hagege AA; MVP-France, Jeunemaitre X


*: First authors


           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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