VLDL/LDL代谢通路基因遗传变异与脑出血易感性的分子流行病学研究

Dyslipidemia is an independent risk factor of cerebral hemorrhage(CH); genetic variations of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) metabolism pathway genes are associated with risk factors of CH; supported by our previous National Natural Science Foundation of China, we found preliminarily that three common polymorphisms of apolipoprotein B and AI gene were related to CH. So we speculate that genetic variations of VLDL/LDL metabolism pathway genes may be related to CH, and may by affecting risk factors of CH such as blood lipid level. This study is to verify this hypothesis in CH families and population study. We will sequencing and genotyping exons of the six target genes in VLDL/LDL metabolism pathway using Solexa sequencing method etc., and find out their all rare and common genetic variations; do the transmission disequilibrium test (TDT) and association study using advanced statistical softwares such as FBAT, SPSS, Haploview and PHASE; analyze the relationship among the risk factors, genetic variations and CH susceptibility by taking advantage of the statistical model of Proportial-Hazards and Logistic Regression analysis. This research, which explores the potential mechanism of CH at molecular level, will be of benefit for specifying the genetic essence and setting up solid foundation of the treatment and prevention of CH.

研究表明脂质代谢紊乱是脑出血的重要危险因素，VLDL/LDL代谢通路基因遗传变异与其相关；我们前期研究发现Apo B、AI基因3个常见多态与脑出血有关。故提出假说：VLDL/LDL代谢通路基因遗传变异可能与脑出血相关，并可能通过影响血脂水平等脑出血危险因素发生作用。本研究拟在脑出血家系及人群中，对VLDL/LDL代谢通路目标基因外显子区域用Solexa、SNPTools等方法进行测序及分型，筛查所有稀有及常见变异；用FBAT、SPSS、Haploview、PHASE软件进行TDT检验和关联分析；用比例-风险回归模型、logistic回归模型等多因素分析法进行统计分析，确认直接或通过修饰脑出血重要危险因素而影响脑出血发生的遗传变异，明确遗传-表型及遗传×环境-表型关系，从分子水平探讨脑出血的可能发病机理，对脑出血易感个体的早期检出和预防具有重要意义，为防治脑出血提供坚实的理论依据和实践指导。

研究表明脂质代谢紊乱是脑出血的重要危险因素，VLDL/LDL代谢通路基因遗传变异与其相关；我们前期研究发现Apo B、AI基因3个常见多态与脑出血有关。故提出假说：VLDL/LDL代谢通路基因遗传变异可能与脑出血相关，并可能通过影响血脂水平等脑出血危险因素发生作用。本项目较好的完成了研究计划，确认了直接或通过修饰脑出血重要危险因素而影响脑出血发生的相关遗传变异，明确了其遗传-表型及遗传×环境-表型关系，相关成果已发表SCI论文3篇、已接收待发表SCI论文2篇，另有已投稿待审稿意见SCI论文3篇，本项目其他研究成果在结题后三年内将继续向自然科学基金委提供。本研究从分子水平探讨了脑出血的可能发病机理，对脑出血易感个体的早期检出和预防具有重要意义，为防治脑出血提供坚实的理论依据和实践指导。