Comprehensive Analysis of Genetic Factors in Diabetes Mellitus

合作研究收集了2195名糖尿病患者和1836名非糖尿病对照组的DNA样本，并将临床信息收集到数据库中。发现胰淀素S20G与2型糖尿病相关。共检测了33个α、β、α、ISL-1、PDX1、NGN3、PAX6、NKX2.2、NKX6.1、Beta2、SUR1和Kir6.2的SNP，并进行了关联研究。开发了微阵列，每个微阵列由来自人或小鼠胰岛的20,000个EST组成。在1型糖尿病动物模型中发现了一个主要的易感基因Cblb。研究2组(基因功能分析)阐明了钾通道对胰岛素分泌、2型糖尿病和血糖稳态的贡献、NADH穿梭系统对胰岛素分泌的贡献、PPARγ对肥胖和胰岛素抵抗的贡献、IRS-2对糖尿病的贡献、脂联素对胰岛素抵抗的贡献以及CREB/ATF家族对糖尿病的贡献。鉴定了新的cAMP感受器cAMP-GEFII，并确定了其在胰岛素分泌中的功能。研究3(疾病状态基因分析)WFS1被确定为Wolfram综合征的相关基因，并明确了其亚细胞定位。GIP信号被发现与肥胖和糖尿病有关。研究4(遗传流行病学)阐明了γ-4α、β-1、ISL-1、Pax4和Synaxin 1A与2型糖尿病的关系。一种用于复杂疾病遗传分析的新方法正在开发中。

COLLABORATIVE STUDIESDNA samples from 2,195 diabetic patients and 1,836 non-diabetic control subjects were collected and the clinical information was collected in a database. Association of amylin S20G with type 2 diabetes was found. A total of 33 SNPs of HNF-1α, HNF-1β, HNF-4α, Isl-1, PDX1, NGN3, PAX6, NKX2.2, NKX6.1, BETA2, SUR1, and Kir6.2 were genotyped and association study is now being performed.Study group 1 (analysis of gene structure)Association of SHP with mild obesity was found. Microarrays, each consisting of 20,000 ESTs from human or mouse islets, were developed. A major susceptibility gene Cblb was identified in an animal model of type 1 diabetes.Study group 2 (analysis of gene function)The contribution of the K_<ATP> channel to insulin secretion, type 2 diabetes and glucose homeostasis, the contribution of the NADH shuttle system to insulin secretion, the contribution of PPARγ to obesity and insulin resistance, the contribution of IRS-2 to diabetes, the contribution of adiponectin to insulin resistance, and the contribution of CREB/ATF family to diabetes were clarified. The novel cAMP sensor cAMP-GEFII was identified and its functional role in insulin secretion was determined.Study group 3 (analysis of genes in disease states)WFS1 was identified as the gene involved in Wolfram syndrome, and its subcellular localization was clarified. GIP signaling was found to be associated with both obesity and diabetes. The roles of PPARγ and PI3-K in insulin action also were clarified.Study group 4 (genetic epidemiology)Associations of HNF-4 α, HNF-1 β, Isl-1, Pax4, and syntaxin1A with type 2 diabetes were clarified. A novel method for the genetic analysis of complex diseases is being developed.