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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

https://doi.org/10.1038/ng.3383
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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