Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure.,Nature Communications

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Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure.
Nature Communications ( IF 14.7 ) Pub Date : 2020-02-28 , DOI: 10.1038/s41467-020-14843-7
Marios Arvanitis _{1,

2} , Emmanouil Tampakakis ₂ , Yanxiao Zhang ₃ , Wei Wang ₄ , Adam Auton ₄ , , Diptavo Dutta _{1,

5} , Stephanie Glavaris ₂ , Ali Keramati ₂ , Nilanjan Chatterjee _{5,

6} , Neil C Chi _{7,

8} , Bing Ren _{3,

8} , Wendy S Post _{2,

9} , Alexis Battle ₁

Affiliation

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.

中文翻译：

全基因组关联和多组学分析显示 ACTN2 是与心力衰竭相关的基因。

心力衰竭是一个主要的公共卫生问题，影响着全球超过 2300 万人。在这项研究中，我们展示了对心力衰竭 GWAS 和类似规模队列中的复制进行的大规模荟萃分析的结果，以确定一个与心力衰竭相关的已知基因座和两个新基因座。心力衰竭亚表型显示，1 号染色体中的新位点与左心室不良重塑和临床心力衰竭有关，以响应不同的初始心肌损伤。该基因座的功能表征和精细定位揭示了心肌细胞分化过程中激活的心肌特异性调节区域中的推定因果变异，该调节区域与 ACTN2 基因结合，ACTN2 基因是心肌肌膜内的关键结构蛋白（Hi-C 相互作用 p 值 = 0.00002）。人胚胎干细胞衍生的心肌细胞中的基因组编辑证实了已鉴定的调节区域对 ACTN2 表达的影响。我们的发现扩展了我们对心力衰竭生物学机制的理解。

更新日期：2020-02-28

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