A Common Variant of ARRB2 Promoter Region Associated with the Prognosis of Heart Failure

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> A total of 2,386 hospitalized patients with chronic HF were enrolled as the first cohort and followed up for a mean period of 20.2 months. Meanwhile, ethnically and geographically matched 3,000 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 analyses were conducted to illuminate the underlying mechanism. <b><i>Results:</i></b> We identified a common variant rs75428611 associated with the prognosis of HF in two-stage population: adjusted <i>p</i> = 0.001, hazard ratio (HR) = 1.31 (1.11–1.54) in additive model and adjusted <i>p</i> = 0.001, HR = 1.39 (1.14–1.69) in dominant model in first-stage population; adjusted <i>p</i> = 0.04, HR = 1.41 (1.02–1.95) in additive model and adjusted <i>p</i> = 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. <b><i>Conclusions:</i></b> Our findings demonstrated that rs75428611 in promoter of ARRB2 was associated with the risk of HF mortality. It is a promising potential treatment target for HF.