β2肾上腺素能受体基因多态性Arg16Gly影响慢性心衰预后及 β受体阻滞剂疗效的机制研究

Chronic heart failure (HF) is the end-stage of various cardiovascular diseases and the main cause of deaths. It is becoming a heavy medical burden and social problem all around the world. In past decades, clinical application of β-blockers remarkably improved the prognosis of HF and enhanced survival of HF patients. However, additional evidences suggest that response to β-blockers varies widely among individuals and genetic variation involved in β-adrenergic receptor signaling pathway is suspected to account for a significant part of this heterogeneity. In our previous study, a total of 2403 hospitalized patients with chronic HF were enrolled in a multicenter observational study and followed up for a mean period of 20.3 months. Genes for β1AR, β2AR, and the major cardiac G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 were analyzed to identify SNPs, and patients were stratified according to genotypes. We found that the common Arg16Gly variation in ADRB2 gene significantly increased the risk of cardiovascular events in HF patients. βAR-blocker therapy markedly improved the long-term prognosis in patients harboring Gly16, rather than Arg16 homozygotes. These observations were successfully replicated in another independent cohort of 919 chronic HF patients. Based on the literature reports and our previous work, we aimed, in this study, to investigate the mechanism of ADRB2 Arg16Gly dictating the β-blocker related outcomes of heart failure through knock-in rat models in vivo and cell systems in vitro. The research results of this study will provide important theoretical basis for the risk stratification management of heart failure, precise medical treatment and the development of new drug targets, which is of great guiding significance for the clinical practice of heart failure.

心竭是多种心血管疾病的终末阶段和最主要的死因，因其发病率高，死亡率高，是全世界面对的社会难题和沉重的医疗负担。临床研究证明，选择性β1受体阻滞剂的应用显著的改善了心衰的预后，但进一步的研究发现心衰患者对于β受体阻滞剂的治疗反应存在差异，β肾上腺素能系统基因多态性可能起到了重要的修饰作用。我们前期在大于3000例心衰患者的大型队列研究中，发现β2受体基因ADRB2 Arg16Gly位点基因多态性影响了心衰的预后和β受体阻滞剂的疗效。本项目旨在前期工作的基础上，建立ADRB2 Arg16Gly c.46 A>G位点knock-in大鼠模型，从动物水平，细胞水平深入阐明ADRB2 Arg16Gly多态性对心衰发生发展的影响及β受体阻滞剂治疗反应差异的分子机制。本研究的研究成果将对心衰的危险分层管理，精准医疗及新药靶点的研发提供重要的理论依据，为临床心衰的诊疗有重要的指导意义。

心力衰竭（Heart failure，HF），简称心衰，是一种以心脏结构和/或功能异常而导致心脏泵血功能不能满足机体的需要为主要特点的涉及多个组织器官功能紊乱的临床综合征。 随着全球老龄化的趋势，心衰成为全球面对的“流行病”。因其高发病率，高死亡率，成为沉重的医疗和经济负担。心衰相关异质性仍有待进一步研究 心衰的治疗策略仍有待进一步完善。 .在研究的第一阶段，我们通过对100对心衰患者和正常对照进行ADRB1，ADRB2，GRK2和GRK5四个基因外显子及邻近区域的测序。结果显示，四个基因存在5个多态性位点，这些多态性在心衰患者和正常人中的分布没有统计学差异。第二阶段，我们纳入了2403名心衰患者组成的第一人群，和919名心衰患者组成的第二人群。并对这些心衰患者进行了随访（第一人群平均随访时间60个月，第二人群平均随访时间），在我们研究的5个引起氨基酸改变的错意变异中，只有ADRB2 Arg16Gly（A>G）与主要终点事件的发生风险密切相关。G等位基因携带者相比AA野生型患者心源性死亡和心脏移植的风险增高近50%。药物和基因型的联合分析提示β受体阻滞剂能显著改善AG组和GG组的主要终点事件发生风险，并呈现等位基因剂量依赖性（GG组：校正HR = 0.38；95% CI，0.23-0.64，p < 0.001，AG组：校正HR =0.64；95% CI，0.42-0.96，p = 0.03）。而AA组的患者对β受体阻滞剂并没有治疗效应（校正HR= 0.70；95% CI，0.45-1.10，p = 0.121）。AG/GG基因型患者体内β2受体-Gi信号偶联存在缺陷，即Arg16Gly多态性位点影响β2受体下游信号通路的一个功能缺失型变异。.后续，我们在RIP3基因的启动子和5’UTR区共检测到14个常见的变异位点，筛选出了一个有意义的突变位点rs3212247。本研究证明在RIP3启动子上的变异位点rs3212247与心衰患者预后显著相关，rs3212247-C等位基因破坏的SOX17的结合，导致RIP3转录活性及蛋白水平的增加，最终加重心衰的发展，导致不良预后。未来RIP3可能成为一个新的心衰治疗靶点。

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