Genetic association analyses highlight biological pathways underlying mitral valve prolapse

Authors: Dina, Christian; Bouatia-Naji, Nabila; Tucker, Nathan; Delling, Francesca N.; Toomer, Katelynn; Durst, Ronen; Perrocheau, Maelle; Fernandez-Friera, Leticia; Solís Martín, Jorge; Le Tourneau, Thierry; Chen, Ming-Huei; Probst, Vincent; Bossé, YohanPibarot, Philippe; Zelenika, Diana; Lathrop, Mark; Hercberg, Serge; Roussel, Ronan; Benjamin, Emelia J.; Bonnet, Fabrice; Lo, Su Hao; Dolmatova, Elena; Simonet, Floriane; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Le Marec, Hervé; Froguel, Philippe; Ellinor, Patrick T.; Vasan, Ramachandran S.; Bruneval, Patrick; Markwald, Roger R.; Norris, Russell A.; Milan, David J.; Slaugenhaupt, Susan A.; Levine, Robert A.; Schott, Jean-Jacques; Hagege, Albert A.; Jeunemaitre, Xavier
Abstract: Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death1. 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.
Document Type: Article de recherche
Issue Date: October 2015
Open Access Date: Restricted access
Document version: VoR
Permalink: http://hdl.handle.net/20.500.11794/7149
This document was published in: Nature Genetics, Vol. 47, 1206–1211 (2015)
http://dx.doi.org/10.1038/ng.3383
Nature Pub. Co.
Alternative version: 10.1038/ng.3383
http://www.ncbi.nlm.nih.gov/pubmed/26301497
Collection:Articles publiés dans des revues avec comité de lecture

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