Introduction The role of ARRB2 in cardiovascular disease has recently gained increasing attention. However, the association between ARRB2 polymorphisms and heart failure (HF) has not yet been investigated. Methods A total of 2386 hospitalized patients with chronic heart failure were enrolled as the first cohort and followed up for a mean period of 20.2 months. Meanwhile, ethnically and geographically matched 3000 individuals without evidence of HF were included as healthy controls. We genotyped the common variant in ARRB2 gene to identify the association between variant and HF. A replicated independent cohort enrolling 837 patients with chronic HF was applied to validate the observed association. A series of function analysis were conducted to illuminate the underlying mechanism. Results We identified a common variant rs75428611 associated with the prognosis of HF in two-stage population: adjusted P = 0.001, HR = 1.31 (1.11-1.54) in additive model and adjusted P = 0.001, HR = 1.39 (1.14-1.69) in dominant model in first-stage population; adjusted P = 0.04, HR = 1.41 (1.02-1.95) in additive model and adjusted P = 0.03, HR = 1.51 (1.03-2.20) in dominant model in replicated stage. However, rs75428611 did not significantly associate with the risk of HF. Functional analysis indicated that rs75428611‐G allele increased the promoter activity and the mRNA expression level of ARRB2 by facilitating transcription factor SRF binding, but not the A allele. Conclusions Our findings demonstrate that rs75428611 in promoter of ARRB2 is associated with the risk of HF mortality. It is a promising potential treatment target for HF.


中文翻译：

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ARRB2启动子区的常见变异与心力衰竭的预后相关

简介 ARRB2 在心血管疾病中的作用最近受到越来越多的关注。然而，ARRB2 多态性与心力衰竭 (HF) 之间的关联尚未得到研究。方法纳入2386例慢性心力衰竭住院患者作为第一队列，随访平均20.2个月。同时，种族和地理上匹配的 3000 名没有心力衰竭证据的个体被纳入健康对照。我们对 ARRB2 基因中的常见变异进行了基因分型，以确定变异与心力衰竭之间的关联。应用招募 837 名慢性心力衰竭患者的重复独立队列来验证观察到的关联。进行了一系列功能分析以阐明潜在机制。结果我们发现了一个与两阶段人群心力衰竭预后相关的常见变异rs75428611：在加法模型中调整后的P = 0.001，HR = 1.31（1.11-1.54），在加性模型中调整后的P = 0.001，HR = 1.39（1.14-1.69）第一阶段人群中的主导模型；在加性模型中调整P = 0.04，HR = 1.41（1.02-1.95），在复制阶段调整主导模型中P = 0.03，HR = 1.51（1.03-2.20）。然而，rs75428611 与心力衰竭风险没有显着相关性。功能分析表明，rs75428611-G 等位基因通过促进转录因子 SRF 结合来增加 ARRB2 的启动子活性和 mRNA 表达水平，但 A 等位基因则不然。结论 我们的研究结果表明，ARRB2 启动子中的 rs75428611 与心力衰竭死亡风险相关。它是心衰的一个有前景的潜在治疗靶点。