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Genetic association analyses highlight biological pathways underlying mitral valve prolapse
- Dina, Christian;
- Bouatia-Naji, Nabila;
- Tucker, Nathan;
- Delling, Francesca N;
- Toomer, Katelynn;
- Durst, Ronen;
- Perrocheau, Maelle;
- Fernandez-Friera, Leticia;
- Solis, Jorge;
- Le Tourneau, Thierry;
- Chen, Ming-Huei;
- Probst, Vincent;
- Bosse, Yohan;
- Pibarot, 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
- et al.
Published Web Location
https://doi.org/10.1038/ng.3383Abstract
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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