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 Bonnet; Su 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

doi:10.1038/ng.3383

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

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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 language	English (US)
Pages (from-to)	1206-1211
Number of pages	6
Journal	Nature Genetics
Volume	47
Issue number	10
DOIs	https://doi.org/10.1038/ng.3383
State	Published - Sep 29 2015
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Dina, C., Bouatia-Naji, N., Tucker, N., Delling, F. N., Toomer, K., Durst, R., Perrocheau, M., Fernandez-Friera, L., Solis, J., Le Tourneau, T., Chen, M. H., Probst, V., Bosse, Y., Pibarot, P., Zelenika, D., Lathrop, M., Hercberg, S., Roussel, R., Benjamin, E. J., ... 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

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

@article{6ba9d3a75845449285c022cf3044713b,

title = "Genetic association analyses highlight biological pathways underlying mitral valve prolapsed",

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.",

author = "Christian Dina and Nabila Bouatia-Naji and Nathan Tucker and Delling, {Francesca N.} and Katelynn Toomer and Ronen Durst and Maelle Perrocheau and Leticia Fernandez-Friera and Jorge Solis and {Le Tourneau}, Thierry and Chen, {Ming Huei} and Vincent Probst and Yohan Bosse and Philippe Pibarot and Diana Zelenika and Mark Lathrop and Serge Hercberg and Ronan Roussel and Benjamin, {Emelia J.} and Fabrice Bonnet and Lo, {Su Hao} and Elena Dolmatova and Floriane Simonet and Simon Lecointe and Florence Kyndt and Richard Redon and {Le Marec}, Herv{\'e} and Philippe Froguel and Ellinor, {Patrick T.} and Vasan, {Ramachandran S.} and Patrick Bruneval and Markwald, {Roger R.} and Norris, {Russell A.} and Milan, {David J.} and Slaugenhaupt, {Susan A.} and Levine, {Robert A.} and Schott, {Jean Jacques} and Hagege, {Albert A.} and Xavier Jeunemaitre",

note = "Publisher Copyright: {\textcopyright} 2015 Nature America, Inc.",

year = "2015",

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doi = "10.1038/ng.3383",

language = "English (US)",

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T1 - Genetic association analyses highlight biological pathways underlying mitral valve prolapsed

AU - Dina, Christian

AU - Bouatia-Naji, Nabila

AU - Tucker, Nathan

AU - Delling, Francesca N.

AU - Toomer, Katelynn

AU - Durst, Ronen

AU - Perrocheau, Maelle

AU - Fernandez-Friera, Leticia

AU - Solis, Jorge

AU - Le Tourneau, Thierry

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

AU - Froguel, Philippe

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

PY - 2015/9/29

Y1 - 2015/9/29

N2 - 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.

AB - 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.

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JF - Nature Genetics

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ER -

Genetic association analyses highlight biological pathways underlying mitral valve prolapsed

Abstract

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