Highlighting Genetic Differences between Barlow’s Disease and Fibroelastic Deficiency via Genome-Wide Association Study Meta-Analyses

Background: Subtypes of mitral valve prolapse (MVP) show a broad spectrum, including the phenotypes fibroelastic deficiency (FED) and Barlow’s disease. However, the underlying genetic differences have not yet been analyzed in detail. This study highlights novel risk loci specific for FED and Barlow’s disease, respectively.

Methods: The cohort included all consecutive patients who underwent mitral valve surgery for degenerative MVP at the Department of Cardiovascular Surgery or presented with symptomatic MVP at the Department of Cardiology at the German Heart Center Munich between March 2002 and January 2021. The cohort was subdivided into the phenotypes FED and Barlow’s disease, based on clinical and morphological characteristics. Intermediate phenotypes were excluded from the subgroup analysis. Subgroups were analyzed via GWAS and investigated in meta-analyses with GWAS datasets stratified from data from the MVP France study. Phenome-wide association study (PheWAS) was performed with datasets from UK Biobank.

Results: Within our cohort of 2,140 MVP patients, 84.5% (n = 1,809) suffered from severe mitral regurgitation that required surgery. The MVP France cohort included 1,412 patients and 2,439 controls, resulting in 3,552 patients and 11,439 controls included in our analyses. GWAS meta-analysis included 997 FED cases and 788 Barlow’s disease cases. Two genome-wide significant loci (p < 5e-8) associated with Barlow’s disease were identified. For Barlow’s disease, 35 further SNPs also showed a significant correlation (p < 5e-5) in 32 risk loci. In association with FED, one highly significant (p < 5e-8) locus was identified. Further 35 SNPs showed a significant FED correlation (p < 5e-5) in 30 risk loci. PheWAS revealed an association with paroxysmal supraventricular tachycardia for one locus correlating with FED on chromosome 4 and for one locus correlating with Barlow’s disease on chromosome 10. Also, associations with left ventricular hypertrophy and ventricular arrhythmia were revealed for risk loci that correlate with Barlow’s disease.

Conclusion: This study presents the first GWAS identifying risk loci associated with FED and Barlow’s disease. PheWAS links lead SNPs to several other cardiac conditions. These findings could initiate a paradigm shift in understanding the genetic differences between FED and Barlow’s disease.

Publikationsverlauf

Artikel online veröffentlicht:
11. Februar 2025