全基因组关联和多组学分析揭示 ACTN2 是与心力衰竭相关的基因。
Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure.
机构信息
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
出版信息
Nat Commun. 2020 Feb 28;11(1):1122. doi: 10.1038/s41467-020-14843-7.
Heart failure is a major public health problem affecting over 23 million people worldwide. In this study, we present the results of a large scale meta-analysis of heart failure GWAS and replication in a comparable sized cohort to identify one known and two novel loci associated with heart failure. Heart failure sub-phenotyping shows that a new locus in chromosome 1 is associated with left ventricular adverse remodeling and clinical heart failure, in response to different initial cardiac muscle insults. Functional characterization and fine-mapping of that locus reveal a putative causal variant in a cardiac muscle specific regulatory region activated during cardiomyocyte differentiation that binds to the ACTN2 gene, a crucial structural protein inside the cardiac sarcolemma (Hi-C interaction p-value = 0.00002). Genome-editing in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2. Our findings extend our understanding of biological mechanisms underlying heart failure.
心力衰竭是一个全球性的重大公共卫生问题，影响着全球超过 2300 万人。在这项研究中，我们对心力衰竭的 GWAS 进行了大规模的荟萃分析，并在一个可比大小的队列中进行了复制，以确定一个已知和两个新的与心力衰竭相关的位点。心力衰竭亚表型研究表明，染色体 1 上的一个新位点与左心室不良重构和临床心力衰竭有关，这是对不同初始心肌损伤的反应。该位点的功能特征和精细映射揭示了一个潜在的因果变异，位于心肌细胞分化过程中激活的心肌特异性调节区域，该区域与 ACTN2 基因结合，后者是心肌细胞膜（Hi-C 相互作用 p 值 = 0.00002）内的关键结构蛋白。在人类胚胎干细胞衍生的心肌细胞中的基因组编辑证实了所鉴定的调节区域对 ACTN2 表达的影响。我们的研究结果扩展了我们对心力衰竭潜在生物学机制的理解。
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