Conditional GWAS analyses for <i>SVIL</i> locus.

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.研究目的 心力衰竭（Heart failure, HF）是一类由多种生物学过程异常引发的严重心血管疾病，全球受累人群超6400万。本研究旨在加深对东亚人群中HF及更特异性的非缺血性心肌病（nonischemic cardiomyopathy, NICM）亚型遗传基础的理解，并解析亚临床左心室功能不全背后的生物学通路。 方法与结果 本研究针对东亚人群的全因HF开展全基因组关联研究（genome-wide association studies, GWAS）荟萃分析（病例数约13385例），同时在多遗传祖先人群中针对定义更精准的NICM亚型进行分析（病例数约3603例）。我们鉴定出一个在东亚人群中富集的低频编码变异，该变异位于MYBPC3基因附近，同时发现了一个NICM特异性位点。后续分析显示，MYBPC3位点存在男性特异性的HF关联，并指出SVIL可作为NICM的候选因果基因。此外，我们证实，在苯肾上腺素（phenylephrine, PE）处理的H9C2细胞中，SVIL缺失会加重心肌细胞肥大、凋亡并降低细胞活力。另外，被视为HF核心标志物的B型利钠肽（B-type natriuretic peptide, BNP）的基因表达水平，在PE刺激的H9C2细胞中经SVIL沉默后进一步升高。对H9C2细胞的RNA测序（RNA-sequencing）分析显示，SVIL的功能可能通过与心肌细胞调控和分化相关的通路介导。 结论 本研究结果加深了我们对东亚人群HF遗传结构的理解，并为NICM背后的生物学通路以及MYBPC3位点的性别特异性关联提供了重要见解，该关联有待在其他数据集中进一步验证。