Comprehensive Analysis of Genetic Factors in Diabetes Mellitus

收集了2,195名糖尿病患者和1,836名非糖尿病对照受试者的DNA样本，并将临床信息收集到数据库中。发现胰淀素S20 G与2型糖尿病相关，共检测到HNF-1α、HNF-1β、HNF-4α、Isl-1、PDX 1、NGN 3、PAX 6、NKX2.2、NKX6.1、BETA 2、SUR 1、Kir6.2等33个SNP，目前正在进行关联性研究。（基因结构分析）发现SHP与轻度肥胖相关。开发了微阵列，每个微阵列由来自人类或小鼠胰岛的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，研究组2（基因功能分析）K_<ATP>通道对胰岛素分泌、2型糖尿病和葡萄糖稳态的作用，NADH穿梭系统对胰岛素分泌的作用，PPARγ对肥胖和胰岛素抵抗的作用，IRS-2对糖尿病的作用，阐明了脂联素在胰岛素抵抗中的作用，以及CREB/ATF家族在糖尿病中的作用。新的cAMP传感器cAMP-GEFI被鉴定，并确定其在胰岛素分泌中的功能作用。研究组3（疾病状态下的基因分析）WFS 1被鉴定为与Wolfram综合征有关的基因，并阐明了其亚细胞定位。GIP信号被发现与肥胖和糖尿病有关。研究组4（遗传流行病学）阐明了HNF-4 α、HNF-1 β、Isl-1、Pax 4和syntaxin 1A与2型糖尿病的关系。目前正在开发一种用于复杂疾病遗传分析的新方法。

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.