血脂相关基因的遗传变异与冠心病易感性的关联研究

Higher plasma low-density lipoprotein cholesterol and total cholesterol levels are well-established risk factors for coronary heart disease (CHD). Recent genome-wide association studies (GWAS) have identified several genes and genetic variants that are associated with lipids levels in Chinese Han population. In this study, we aim to identify the association between lipid-associated genetic variants in our previous GWAS and CHD susceptibility in Chinese. We conducte a two-stage case-control study from the two independent populations in different regions: Chongqing and Wuhan. Each stage consists of 1000 CHD cases and 1000 controls. All subjects in our study have complete environment exposure information, including diet, smoking, drinking and physical activity. In the present study, we examine the potential interactions between the genetic factors and environment exposure in relation to CHD risk. Furthermore, we calculated a genotype risk score (GRS) to assess cumulative effects of genetic variants on CHD risk. The combination of the major genetic risk factors may contribute to the CHD risk and will be useful in screening for high-risk populations. In addition, we performed a functional test to explore the potential biological mechanism of the causal variants. This study combines epidemiologic study and functional investigation. It will comprehensively demonstrate that the genes, lipids and environment factors play a pivotal role in the development of CHD. It will be useful for the early detection and treatment of CHD, thus enabling early preventive strategies.

血浆低密度脂蛋白和总胆固醇水平升高是冠心病发病的重要危险因素。基于本课题组前期对中国汉族人血脂水平的全基因组关联研究（GWAS）结果，本项目拟采用多中心两阶段的关联研究策略，分别在重庆和武汉建立1000对冠心病的病例对照生物样本库，并了解各个研究对象的环境（如饮食、吸烟、饮酒、体力活动等）暴露情况。拟通过两阶段的病例对照研究，对GWAS鉴定的血脂相关基因的遗传变异与冠心病易感性的关联性进行系统研究，通过遗传风险评分模型进一步探讨多个易感基因对冠心病发病风险的累积效应，重点探讨基因-环境交互作用与冠心病易感性的关系；同时结合生物信息学和分子生物学技术，对冠心病易感基因的遗传变异进行生物学机制的探讨。本研究通过人群流行病学和实验室研究，系统阐明血脂、遗传与环境等因素在冠心病发生发展中的作用，为冠心病高危人群预警和提出合理的个体化干预方案提供重要依据。

血脂和遗传是冠心病发病的两大重要病因，近年来全基因组关联研究（GWAS）发现和鉴定了一批与血脂水平相关的易感基因和遗传变异，但是这些新基因对冠心病发病的影响和机制尚不完全清楚。本研究紧随后GWAS研究时代的需要，采用中通量基因分型技术、分子生物学、分子流行病学等方法系统全面地分析了血脂相关基因与冠心病易感性的关系。本研究在重庆新建2000多对冠心病病例对照生物样本库的基础上，采用多中心两阶段的研究策略发现并证实了TRIB1、APOA4-APOA5-ZNF259-BUD13、SLC22A3-LPAL2-LPA、ADAMTS7、ABO等多个基因对血脂和冠心病的影响，交互作用和累积效应的分析也进一步证实了遗传和环境因素对冠心病的发生发展有重要作用。由8个血脂相关的阳性位点构建的基因型评分模型显示，多个危险等位基因的累积效应显著提高了危险血脂的水平，从而增加冠心病的发病风险。我们新发现TRIB1上的rs17321515和SLC22A3-LPAL2-LPA基因簇上的rs3088442、rs7767084 和rs10755578均能显著增加中国汉族人冠心病的发病风险。进一步的生物信息学和分子生物学研究发现，rs3088442遗传变异通过破坏microRNA的结合位点，使相应基因SLC22A3和LPA的表达量增高，从而增加了血浆Lp(a)的水平，最终导致冠心病的发生。本研究阐明了血脂相关基因遗传变异与中国汉族人群冠心病遗传易感性的相关性，研究所发现的与我国人群血脂和冠心病相关的易感基因有望作为分子标志物用于筛选高危人群或易感个体，对冠心病的早期诊断和治疗预后具有重要的现实意义。