Medical Research Council MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Nat Genet. 2013 Jun;45(6):621-31. doi: 10.1038/ng.2610. Epub 2013 Apr 14.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
静息心率升高与心血管疾病和死亡率风险增加相关。在一项对多达 181171 人的全基因组关联研究的两阶段荟萃分析中，我们发现了 14 个与心率相关的新位点，并确认了与所有 7 个先前确定的位点的关联。在果蝇和斑马鱼中的基因表达下调实验鉴定出 11 个位点的 20 个基因与心率调节相关，突出了信号转导、胚胎心脏发育以及扩张型心肌病、先天性心力衰竭和/或心源性猝死的病理生理学相关基因的作用。此外，心率升高的遗传易感性与心脏传导改变和病态窦房结综合征风险降低相关，而增加和降低心率的变异与心房颤动风险相关。我们的研究结果为调节心率的机制提供了新的见解，并确定了新的治疗靶点。
