Genome-wide analysis identifies novel susceptibility loci for heart failure and nonischemic cardiomyopathy subtype

Abstract

Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes that affects over 64 million people worldwide. Here, we report a meta-analysis of genome-wide analysis for all-cause HF in East Asian populations (n ~ 227,000) and more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (n ~ 403,000). We identified 3 previously unknown HF loci and 2 NICM loci. Follow up analyses demonstrated male-specific HF association at CDKN1A and MYBPC3 loci, and prioritized candidate causal gene at SVIL locus for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis on H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results further elucidate the genetic architecture of HF and provide important insight into the biological pathways underlying NICM and sex-specific relevance of CDKN1A and MYBPC3 loci.