PPARA相关rSNP的组学筛查及其在高胆固醇血症中的协同致病机制

Hypercholesterolaemia (HC) is a complex disorder characterized by raised serum total cholesterol (TC) and LDL cholesterol levels, and associated with an increased risk of atherosclerosis and coronary heart disease. It is a common assumption that HC is caused by genetic factors, environmental factors and the interaction of the two. Based on the genome-wide scanning, more and more rSNP (regulatory SNP) related to cholesterol-trait had been detected. Recently, our group found that rSNP potentially contributed to the dysfunction of gene regulation among PPARA and its’ targets. In this study, we will be focused on construct the cholesterol-trait related genetic regulatory network (GRN) using ChIP-sequencing and RNA microarray resource; as well as a list of rSNP related to HC based on individual SNP-typing data. Most import, the integration of regulatory profiles and genetic map will illuminate the pathogenesis of the HC in population. And, the role of rSNP on cholesterol-trait will be confirmed in HepG2 cell line models. The completion of this project will further clarify the contribution of gene regulation in metabolic dyslipidemia, which will provide a novel health promotion strategy for coronary heart disease.

高胆固醇血症（Hypercholesterolemia, HC）是一种以血浆总胆固醇和低密度脂蛋白胆固醇明显增高为特征的复杂疾病，是心血管病的重要危险因素。目前已知HC与遗传因素有关。组学筛查表明，人群胆固醇性状关联位点多数是调控性单核苷酸多态性（regulatory SNP,rSNP），可影响基因表达调控。PPARA作为重要的脂质感受器是Fibrate类降血脂的作用靶点。我们的研究提示，rSNP可影响PPARA与其靶基因协同过程，从而导致HC。据此，本项目拟整合多层次组学数据，系统预测PPARA有关rSNP；在建立HC遗传资源库的基础上，验证PPARA有关rSNP与HC关联；进一步在人群和细胞模型两个层次，探讨rSNP参与多基因协同致病的过程。本项目将完善基于多基因协同的复杂疾病研究方案，揭示HC发生的分子机制，为冠心病的控制提供新思路。

高胆固醇血症（Hypercholesterolemia, HC）是冠心病的独立危险因素。我们的研究证实：PPARA可通过调控靶基因表达影响肝细胞的胆固醇代谢过程；调控元件（如 TFBS）中的多态性是影响 PPARA 信号通路的重要因素。本项目进一步以HepG2为模型，整合多层次组学数据构建了38,797个“TF-TFBS-Targets”调控过程；并通过分析149种药物处理HepG2后的转录组数据，筛选可以干预 HC相关调控过程的药物；并通过实验证实组蛋白去乙酰化酶抑制剂（HDACI，如 SAHA）可以治疗“PPARA- TFBS- DGAT2”调节紊乱所导致的高脂血症及其并发症。