Genetic association analyses highlight biological pathways underlying mitral valve prolapse.
Christian DinaNabila Bouatia-NajiNathan TuckerFrancesca N DellingKatelynn ToomerRonen DurstMaelle PerrocheauLeticia Fernandez-FrieraJorge Solisnull nullThierry Le TourneauMing-Huei ChenVincent ProbstYohan BossePhilippe PibarotDiana ZelenikaMark LathropSerge HercbergRonan RousselEmelia J BenjaminFabrice BonnetSu Hao LoElena DolmatovaFloriane SimonetSimon LecointeFlorence KyndtRichard RedonHervé Le MarecPhilippe FroguelPatrick T EllinorRamachandran S VasanPatrick BrunevalRoger R MarkwaldRussell A NorrisDavid J MilanSusan A SlaugenhauptRobert A LevineJean-Jacques SchottAlbert A Hagegenull nullXavier Jeunemaitrenull nullPublished in: Nature genetics (2015)
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.
Keyphrases
- mitral valve
- genome wide association
- left ventricular
- genome wide
- heart failure
- aortic stenosis
- left atrial
- aortic valve
- transcription factor
- case control
- poor prognosis
- dna methylation
- cardiac resynchronization therapy
- binding protein
- mitochondrial dna
- copy number
- type diabetes
- genome wide association study
- transcatheter aortic valve replacement
- urinary incontinence
- atrial fibrillation
- escherichia coli
- staphylococcus aureus
- coronary artery disease
- high fat diet induced
- cystic fibrosis
- protein protein
- small molecule
- amino acid
- wild type
- ejection fraction