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Identification of diabetes-related genes

糖尿病相关基因的鉴定

基本信息

批准号：
12204007
负责人：
HIDEICHI Hideichi
金额：
$ 30.14万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

To identify diabetes susceptibility genes in Japanese, 1) we analyzed the association of single nucleotide polymorphisms (SNPs) and haplotypes of candidate genes with diabetes, 2) we examined factors regulating phosphodiesterase 3B (PDE3B), a promising candidate gene for insulin resistance seen with type 2 debates. In type 1 diabetes, we conducted a clinical study called "Ehime Study" where we screened a large number of diabetic subjects using glutamic acid decarboxylase antibody, a marker for self-immune-mediated diabetes. We classified GAD positive subjects into insulin-deficient and non-insulin-deficient groups, and elucidated characteristics of adult type 1 diabetes. In type 2 diabetes, we analyzed SNPs of candidate genes such as insulin, insulin receptor, and FOXC2 using cases and controls, but no significant association was evident. Then, we focused on resistin, a cytokine inducing insulin resistance. Its promoter SNP at-420 was found to be a type 2 diabetes susceptibility gene. The G/G genotype was associated with type 2 diabetes with odds ratio about two. In functional analysis, Sp1/3 transcription factors specifically recognized G at-420, and enhanced the resistin promoter activity. In humans, serum and monocyte mRNA levels of resistin was highest in the G/G genotype, followed by C/G, and C/C. In terms of adipocyte PDE3B, its gene expression was reduced in obese insulin-resistant mice. PDE3B gene expression was positively regulated by peroxisome proliferator-activated receptor γ (PPARγ) and adipocyte differentiation, and negatively regulated by adipocyte size in vitro. We also identified 14-3-3 protein as an interacting factor with PDE3B. We also cloned PDE3B gene promoter, and analyzed its SNPs but they were not associated with type 2 diabetes.

为了确定日本人的糖尿病易感基因，1）我们分析了单核苷酸多态性（SNP）和候选基因的单倍型与糖尿病的关联，2）我们检查了调节磷酸二酯酶3B（PDE 3B）的因素，PDE 3B是2型糖尿病争论中发现的一个有希望的胰岛素抵抗候选基因。在1型糖尿病中，我们进行了一项名为“爱媛研究”的临床研究，在该研究中，我们使用谷氨酸脱羧酶抗体（一种自身免疫介导的糖尿病的标志物）筛选了大量糖尿病受试者。我们将GAD阳性者分为胰岛素缺乏和非胰岛素缺乏两组，并阐明了成人1型糖尿病的特征。在2型糖尿病中，我们分析了候选基因如胰岛素、胰岛素受体和FOXC 2的SNP，使用病例和对照，但没有明显的关联。然后，我们重点研究了一种诱导胰岛素抵抗的细胞因子--β-葡聚糖。其启动子-420位点的SNP被认为是2型糖尿病易感基因。G/G基因型与2型糖尿病相关，优势比约为2。在功能分析中，Sp1/3转录因子特异性识别Gat-420，并增强了Gin启动子的活性。在人类中，G/G基因型的血清和单核细胞中的GABN mRNA水平最高，其次是C/G和C/C。在脂肪细胞PDE 3B方面，其基因表达在肥胖胰岛素抵抗小鼠中减少。PDE 3B基因表达受过氧化物酶体增殖物激活受体γ（PPARγ）和脂肪细胞分化的正调控，受脂肪细胞大小的负调控。我们还鉴定了14-3-3蛋白作为与PDE 3B相互作用的因子。我们还克隆了PDE 3B基因启动子，并分析了其SNPs，但它们与2型糖尿病无关。