Genetic association analyses highlight biological pathways underlying mitral valve prolapsed

Christian Dina, Nabila Bouatia-Naji, Nathan Tucker, Francesca N. Delling, Katelynn Toomer, Ronen Durst, Maelle Perrocheau, Leticia Fernandez-Friera, Jorge Solis, Thierry Le Tourneau, Ming Huei Chen, Vincent Probst, Yohan Bosse, Philippe Pibarot, Diana Zelenika, Mark Lathrop, Serge Hercberg, Ronan Roussel, Emelia J. Benjamin, Fabrice BonnetSu Hao Lo, Elena Dolmatova, Floriane Simonet, Simon Lecointe, Florence Kyndt, Richard Redon, Hervé Le Marec, Philippe Froguel, Patrick T. Ellinor, Ramachandran S. Vasan, Patrick Bruneval, Roger R. Markwald, Russell A. Norris, David J. Milan, Susan A. Slaugenhaupt, Robert A. Levine, Jean Jacques Schott, Albert A. Hagege, Xavier Jeunemaitre

Research output: Contribution to journalArticle

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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 â '/â ' 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.

Original languageEnglish (US)
Pages (from-to)1206-1211
Number of pages6
JournalNature Genetics
Volume47
Issue number10
DOIs
StatePublished - Sep 29 2015

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Mitral Valve Prolapse
Mitral Valve Insufficiency
Zebrafish
Morpholinos
Inheritance Patterns
Focal Adhesions
Genome-Wide Association Study
Sudden Death
Cytoskeleton
Mitral Valve
Morphogenesis
Cysteine
Meta-Analysis
Transcription Factors
Heart Failure
Phenotype
Genes
Proteins
Tensins

ASJC Scopus subject areas

  • Genetics

Cite this

Dina, C., Bouatia-Naji, N., Tucker, N., Delling, F. N., Toomer, K., Durst, R., ... Jeunemaitre, X. (2015). Genetic association analyses highlight biological pathways underlying mitral valve prolapsed. Nature Genetics, 47(10), 1206-1211. https://doi.org/10.1038/ng.3383

Genetic association analyses highlight biological pathways underlying mitral valve prolapsed. / 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.

In: Nature Genetics, Vol. 47, No. 10, 29.09.2015, p. 1206-1211.

Research output: Contribution to journalArticle

Dina, C, Bouatia-Naji, N, Tucker, N, Delling, FN, Toomer, K, Durst, R, Perrocheau, M, Fernandez-Friera, L, Solis, J, 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 & Jeunemaitre, X 2015, 'Genetic association analyses highlight biological pathways underlying mitral valve prolapsed', Nature Genetics, vol. 47, no. 10, pp. 1206-1211. https://doi.org/10.1038/ng.3383
Dina C, Bouatia-Naji N, Tucker N, Delling FN, Toomer K, Durst R et al. Genetic association analyses highlight biological pathways underlying mitral valve prolapsed. Nature Genetics. 2015 Sep 29;47(10):1206-1211. https://doi.org/10.1038/ng.3383
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. / Genetic association analyses highlight biological pathways underlying mitral valve prolapsed. In: Nature Genetics. 2015 ; Vol. 47, No. 10. pp. 1206-1211.
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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 {\^a} '/{\^a} ' 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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AU - Dina, Christian

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AU - Durst, Ronen

AU - Perrocheau, Maelle

AU - Fernandez-Friera, Leticia

AU - Solis, Jorge

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AU - Chen, Ming Huei

AU - Probst, Vincent

AU - Bosse, Yohan

AU - Pibarot, Philippe

AU - Zelenika, Diana

AU - Lathrop, Mark

AU - Hercberg, Serge

AU - Roussel, Ronan

AU - Benjamin, Emelia J.

AU - Bonnet, Fabrice

AU - Lo, Su Hao

AU - Dolmatova, Elena

AU - Simonet, Floriane

AU - Lecointe, Simon

AU - Kyndt, Florence

AU - Redon, Richard

AU - Le Marec, Hervé

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AU - Ellinor, Patrick T.

AU - Vasan, Ramachandran S.

AU - Bruneval, Patrick

AU - Markwald, Roger R.

AU - Norris, Russell A.

AU - Milan, David J.

AU - Slaugenhaupt, Susan A.

AU - Levine, Robert A.

AU - Schott, Jean Jacques

AU - Hagege, Albert A.

AU - Jeunemaitre, Xavier

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