中国人2型糖尿病全基因组关联研究中发现易感位点的大样本关联研究

项目名称： 中国人2型糖尿病全基因组关联研究中发现易感位点的大样本关联研究

项目编号： No.30800617

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 胡承

作者单位： 上海交通大学

项目金额： 20万元

中文摘要： 课题组前期开展了中国人2型糖尿病全基因组关联研究，在400例样本中检测了约317,000个单核苷酸多态性位点（SNP），对基因型数据质控后，分析比较300,986个SNP在193例2型糖尿病患者和200例正常对照者中的等位基因频率分布，见到分布于40个基因区域上的45个SNP在病例－对照组间频率分布存在显著差异（P<0.0005）。本课题拟以此前期发现为基础，首先在3700例病例－对照样本中对这45个SNP进行检测，开展遗传关联研究，发现疾病易感位点，并从发现的易感位点所在基因区域入选更多SNP，寻找该区域内与2型糖尿病发生最相关的位点并分析其与糖代谢中间性状的关系，同时，从2型糖尿病家系入选样本进行家系关联研究进一步验证该位点与疾病的相关性。本研究对认识中国人2型糖尿病遗传机制具有重要理论意义，并将推动2型糖尿病病因学研究及中国人2型糖尿病遗传流行病学研究的进程。

中文关键词： 2型糖尿病；遗传；基因组；关联研究

英文摘要： Besides our preliminary genome-wide SNP chip data, we collaborated with the Chinese University of Hong Kong and recruited a total of 8000 case-control samples, 248 pedigrees who were suffered type 2 diabetes in Shanghai and 7800 case-control samples, 178 pedigree who were suffered type 2 diabetes in Hong Kong. We further validated the relationship between the two potential loci and type 2 diabetes, and found that the rs10*****3 was associated with type 2 diabetes (p = 2.6×-8). Afterwards, we contacted with collaborators from Japan, Korea, Singapore and United Kingdom, totally enrolled 88,166 different of samples and finally confirmed that there was association between rs10*****3 and type 2 diabetes [P=1.9×-10, OR(95%CI) = 1.10(1.07-1.14)]. Furthermore, we participated in the meta-analysis of genome-wide association studies in East Asians. we collected data from eight genome-wide association studies and identify eight new type 2 diabetes loci ,such as GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. In addition, we performed replication studies on the genes which have shown associations with type 2 diabetes and fasting plasma glucose and insulin levels in other populations. We found that SNPs of PPARG, KCNJ11, TCF2, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2, SLC30A8 and KCNQ1 were associated with type 2 diabetes with OR 1.114~1.532. GCK, G6PC2, MTNR1B, MADD, GIPR, GLIS3 were associated to fasting plasma glucose. Moreover, we performed genetics studies on diabetic microvascular complications and identified CPVL/CHN2 as a diabetic retinopathy susceptibility locus. We also performed a pharmacogenetic study and observed that polymorphisms of KCNQ1 influenced the therapeutic efficacy of repaglinide in Chinese. We totally published 11SCI articles with the support of this project.

英文关键词： type 2 diabetes; genetics; genome; association study