缺血性脑卒中与糖、脂代谢异常的遗传流行病学家系研究

项目名称： 缺血性脑卒中与糖、脂代谢异常的遗传流行病学家系研究

项目编号： No.30872173

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 生物科学

项目作者： 胡永华

作者单位： 北京大学

项目金额： 30万元

中文摘要： 本研究以社区为基础建立了2型糖尿病和缺血性脑卒中患病家系的资料库和生物样本库，探讨炎症反应和氧化应激通路上的多个基因多态性位点及单体型与疾病表型的关系。研究募集到缺血性脑卒中家系192个，2型糖尿病家系284个，另组成了225个代谢综合征家系。本研究在连锁和关联分析中未发现所选基因位点与疾病表型直接相关。交互作用分析发现，在缺血性脑卒中家系的不吸烟人群中，MTHFR 677CT和eNOS 894T的联合作用能使缺血性脑卒中发生风险增加约3倍（P=0.004）。在2型糖尿病家系中，炎症通路的USF，UCP2和TNFα30340;CC-GA-GA/AA 基因型组合是T2DM 发病的保护性因素,基因环境交互作用发现血脂紊乱与TNFα22522;因的联合作用可增加T2DM的发病风险。本研究同时在项目社区进行脑卒中和2型糖尿病等慢性疾病的患病普查，初步掌握了项目社区中老年人群的慢性病流行特征，以上述目标疾病患者作为先证者，通过先证者引荐法继续募集家系。国外全基因组关联研究近年来迅猛发展，新发现的候选基因亟需重复验证，家系研究设计将为识别复杂疾病的易感基因提供更为准确和可靠的途径。

中文关键词： 缺血性脑卒中；2型糖尿病；遗传流行病学；易感基因；交互作用

英文摘要： This study has established the genetic database of community based chronic disease pedigrees, including 192 ischemic stroke pedigrees, 284 type 2 diabetes mellitus pedigrees and 225 metabolic syndrome pedigrees. The family-based design will avoid the "false association" due to small sample size in some hospital-based studies and potential population stratification. No significant results have been found after exploring the association of multi-loci genetic polymorphisms as well as their haplotypes from the inflammation and oxidative stress pathways with the disease phenotypes. However, in the interaction analysis, the MTHFR 677CT and eNOS 894T variants have the synergistic effect to increase the ischemic stroke risk by 3 times (P=0.004). Moreover, it is ascertained that the CC-CA-GA/AA genotype combination of USF, UCP2 and TNFαene will decrease type 2 diabetes risk. TNFαene can also interact with dyslipidemia to promote type 2 diabetes. The screening project of non-communicable diseases has been launched in the study field and more patient families will be recruited by proband-initiated strategy. As the future application of now- and next- generation technologies, e.g. GWAS, the family-based study is expected to provide more powerful evidence on the disease mechanisms and to improve the genetic etiology of complex diseases.

英文关键词： Ischemic stroke; type 2 diabetes; genetic epidemiology; susceptibility genes; interactions