Genetic association analyses highlight biological pathways underlying mitral valve prolapse.
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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(-/-) 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. |
Year of Publication | 2015
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Journal | Nat Genet
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Volume | 47
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Issue | 10
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Pages | 1206-11
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Date Published | 2015 Oct
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ISSN | 1546-1718
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URL | |
DOI | 10.1038/ng.3383
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PubMed ID | 26301497
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PubMed Central ID | PMC4773907
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Links | |
Grant list | MOP-137058 / Canadian Institutes of Health Research / Canada
MOP-126072 / Canadian Institutes of Health Research / Canada
R01-HL127692 / HL / NHLBI NIH HHS / United States
R01 HL127692 / HL / NHLBI NIH HHS / United States
MOP-114997 / Canadian Institutes of Health Research / Canada
K24HL105780 / HL / NHLBI NIH HHS / United States
8P20 GM103444-07 / GM / NIGMS NIH HHS / United States
HL065962 / HL / NHLBI NIH HHS / United States
K24 HL67434 / HL / NHLBI NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
R01 HL72265 / HL / NHLBI NIH HHS / United States
HL109506 / HL / NHLBI NIH HHS / United States
MOP-102481 / Canadian Institutes of Health Research / Canada
R01 HL109004 / HL / NHLBI NIH HHS / United States
MOP-102737 / Canadian Institutes of Health Research / Canada
C06 RR018823 / RR / NCRR NIH HHS / United States
1P30 GM103342 / GM / NIGMS NIH HHS / United States
K23 HL116652 / HL / NHLBI NIH HHS / United States
R01-HL33756 / HL / NHLBI NIH HHS / United States
HL092577 / HL / NHLBI NIH HHS / United States
HL104156 / HL / NHLBI NIH HHS / United States
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