Genome-wide analysis identifies susceptibility loci for heart failure and nonischemic cardiomyopathy subtype in the East Asian populations

Aims: Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. Methods and results: We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N cases ~ 13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene 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 of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. Conclusion: These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Author summary: Heart failure (HF), a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affects over 64 million people worldwide. Both genetic factors and exposure to environmental factors contribute to HF onset, with estimated heritability ranging from 26% to 34%. Genome-wide association studies (GWAS) have identified 106 susceptibility loci for HF, primarily in populations of European ancestry. However, the genetic architecture of HF in the East Asian populations remains to be explored. Therefore, we carried out a meta-analysis of genome-wide analysis for all-cause HF in the East Asian populations and more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations. We identified a low-frequency East-Asian enriched coding variant near the MYBPC3 locus for HF and a NICM specific locus (SVIL). The effect of MYBPC3 on risk of all-cause HF was more pronounced in males than in females. Furthermore, SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. This work tackle the lack of population diversity in GWAS, and provide opportunities for further exploration of the biological mechanisms underlying the pathogenesis of HF and left ventricular remodeling.