冠心病新易感基因RGS5在动脉粥样硬化中的作用机制研究

Genetics plays a key role in the pathogenesis of coronary artery disease (CAD). Through genome wide association study and multi-center validation consisting of 9758 individuals, we identified the SNP rs1056515 located in 3’UTR of RGS5 associated with CAD. Through functional study in vivo, we found that RGS5 was a novel susceptibility gene and the reduction in RGS5 expression exacerbated atherosclerotic lesions. However, the reason of RGS5 downregulation and the underlying mechanism of RGS5 on the development of atherosclerosis remain unknown. Variants found in RGS5 3’UTR of CAD patients decreased RGS5 expression and were predicted to increase the binding of miRNA; Reduced RGS5 increased the expression of adhesion molecules and chemokines and activated NF-κB signal pathway in endothelial cells. Thus, we hypothesize that 1) Both genetic and environmental effects decrease RGS5 gene expression through miRNA, and 2) the decreased RGS5 aggravates endothelial cell activation and exacerbates atherosclerosis, and 3) RGS5 regulates the endothelial cell function through NF-κB signaling pathway. This project is intended to prove this hypothesis using a series of experiments in vivo and in vitro. The results of this project will provide new ideas for the genetic mechanism and targets for the diagnosis and treatment of CAD.

冠心病是遗传和环境共同作用的多基因遗传性疾病。我们前期通过全基因组关联分析和功能验证发现RGS5基因是冠心病新易感基因，斑块组织中RGS5表达下调，敲低RGS5加速粥样斑块形成。但遗传和环境因素如何介导RGS5下调，进而通过何种机制促进动脉粥样硬化发生尚不清楚。预实验发现，冠心病病人RGS5的3’UTR富集降低RGS5表达的罕见变异，预测其将增强miRNA181-5p，miRNA195-5p的结合；敲低RGS5激活NF-κB通路，上调内皮细胞粘附分子和趋化因子表达。基于上述工作，本课题拟利用系列体内外实验开展以下研究：1）遗传变异和环境危险因素如何通过miRNA介导RGS5表达下调；2）下调的RGS5如何调控内皮细胞功能而促进动脉粥样硬化发生；3）RGS5如何通过NF-κB信号通路调控内皮细胞功能，其调控的关键节点分子是什么。项目顺利实施将为冠心病的遗传分子机制和诊疗提供新思路和靶点。

冠心病是威胁人类健康，加重社会负担的重要心血管疾病。冠心病受遗传因素、环境因素以及两者的交互作用共同影响。冠状动脉粥样硬化是冠心病的主要病理过程。然而，冠心病的遗传基础和致病机制目前仍不完全明确。本项目中，我们运用基因组学、分子生物学、细胞生物学等手段，利用规模化的病例-对照队列、病人组织样本及多种小鼠和细胞模型，结合公共数据挖掘，主要发现如下：1）全基因组关联分析结合靶向区域重测序发现冠心病的新易感基因RGS5；2）转录组学结合全基因组关联分析鉴定ROR1为冠心病新易感基因；3）部分明确RGS5在动脉粥样硬化中的作用机制：内外环境危险因素降低RGS5表达，激活NF-κB信号通路，促使内皮细胞活化进而促进动脉粥样硬化形成；另一个重要的动脉粥样硬化相关分子CXCL12也受到RGS5的调控，但具体机制仍需进一步的研究；4）发现miR-223抑制靶基因IL-6的表达调控内皮细胞活化和动脉粥样硬化的进展。发现冠心病的遗传学基础，阐明易感基因在冠状动脉粥样硬化过程中起作用的分子机制对于冠心病的预防、诊断与治疗具有重要临床意义。在本项目支持下共发表科技论文5篇，其中SCI收录论文3篇，总计影响因子32.4，中文核心期刊2篇。