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Genetic association analyses highlight biological pathways underlying mitral valve prolapse.

  • Author(s): Dina, Christian;
  • Bouatia-Naji, Nabila;
  • Tucker, Nathan;
  • Delling, Francesca N;
  • Toomer, Katelynn;
  • Durst, Ronen;
  • Perrocheau, Maelle;
  • Fernandez-Friera, Leticia;
  • Solis, Jorge;
  • PROMESA investigators;
  • 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;
  • MVP-France;
  • Jeunemaitre, Xavier;
  • Leducq Transatlantic MITRAL Network
  • et al.

Published Web Location

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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