Dataset Information

Genetic association analyses highlight biological pathways underlying mitral valve prolapse.

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.

SUBMITTER: Dina C

PROVIDER: S-EPMC4773907 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic association analyses highlight biological pathways underlying mitral valve prolapse.

Dina Christian C Bouatia-Naji Nabila N Tucker Nathan N Delling Francesca N FN Toomer Katelynn K Durst Ronen R Perrocheau Maelle M Fernandez-Friera Leticia L Solis Jorge J Le Tourneau Thierry T Chen Ming-Huei MH Probst Vincent V Bosse Yohan Y Pibarot Philippe P Zelenika Diana D Lathrop Mark M Hercberg Serge S Roussel Ronan R Benjamin Emelia J EJ Bonnet Fabrice F Lo Su Hao SH Dolmatova Elena E Simonet Floriane F Lecointe Simon S Kyndt Florence F Redon Richard R Le Marec Hervé H Froguel Philippe P Ellinor Patrick T PT Vasan Ramachandran S RS Bruneval Patrick P Markwald Roger R RR Norris Russell A RA Milan David J DJ Slaugenhaupt Susan A SA Levine Robert A RA Schott Jean-Jacques JJ Hagege Albert A AA Jeunemaitre Xavier X

Nature genetics 20150824 10

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 ge ...[more]

PMID: 26301497

Similar Datasets

Project description:Background Mitral valve prolapse (MVP) is a common heart valve disease, the most frequent indication for valve repair or replacement. MVP is characterized by excess extracellular matrix secretion and cellular disorganization, which leads to bulky valves that are unable to coapt correctly during ventricular systole resulting in mitral regurgitation, and it is associated with sudden cardiac death. Here we aim to characterize globally the biological mechanisms underlying genetic susceptibility to MVP to better characterize its triggering mechanisms. Methods We applied i-GSEA4GWAS and DEPICT, two pathway enrichment tools to MVP genome-wide association studies. We followed-up the association with MVP in an independent dataset of cases and controls. This research was conducted using the UK Biobank Resource. Immunohistochemistry staining for Glis1 (GLIS family zinc finger 1) was conducted in developing heart of mice. Knockdown of Glis1 using morpholinos was performed in zebrafish animals 72 hours postfertilization. Results We show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of GLIS1, a transcription factor from the Krüppel-like zinc finger family. In combination with previously available data, we now report a genome-wide significant association with MVP (odds ratio, 1.20; P=4.36×10-10), indicating that Glis1 is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves in mouse. We also show that Glis1 knockdown causes atrioventricular regurgitation in developing hearts in zebrafish. Conclusions Our findings define globally molecular and cellular mechanisms underlying common genetic susceptibility to MVP and implicate established and unprecedented mechanisms. Through the GLIS1 association and function, we point at regulatory functions during cardiac development as common mechanisms to mitral valve degeneration.

Project description:BackgroundInitial studies have suggested the familial clustering of mitral valve prolapse, but most of them were either community based among unselected individuals or applied non-specific diagnostic criteria. Therefore little is known about the familial distribution of mitral regurgitation in a referral-type population with a more severe mitral valve prolapse phenotype. The objective of this study was to evaluate the presence of familial mitral regurgitation in patients undergoing surgery for mitral valve prolapse, differentiating patients with Barlow's disease, Barlow forme fruste and fibro-elastic deficiency.MethodsA total of 385 patients (62 ± 12 years, 63% men) who underwent surgery for mitral valve prolapse were contacted to assess cardiac family history systematically. Only the documented presence of mitral regurgitation was considered to define 'familial mitral regurgitation'. In the probands, the aetiology of mitral valve prolapse was defined by surgical observations.ResultsA total of 107 (28%) probands were classified as having Barlow's disease, 85 (22%) as Barlow forme fruste and 193 (50%) patients as fibro-elastic deficiency. In total, 51 patients (13%) reported a clear family history for mitral regurgitation; these patients were significantly younger, more often diagnosed with Barlow's disease and also reported more sudden death in their family as compared with 'sporadic mitral regurgitation'. In particular, 'familial mitral regurgitation' was reported in 28 patients with Barlow's disease (26%), 15 patients (8%) with fibro-elastic deficiency and eight (9%) with Barlow forme fruste (P < 0.001).ConclusionsIn a large cohort of patients operated for mitral valve prolapse, the self-reported prevalence of familial mitral regurgitation was 26% in patients with Barlow's disease and still 8% in patients with fibro-elastic deficiency, highlighting the importance of familial anamnesis and echocardiographic screening in all mitral valve prolapse patients.

Dataset Information

Genetic association analyses highlight biological pathways underlying mitral valve prolapse.

Publications

Genetic association analyses highlight biological pathways underlying mitral valve prolapse.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets