Genetics of Type 2 Diabetes in Starr County, Texas

描述(申请人提供)：2型糖尿病继续无情地攻击健康。大量证据表明遗传因素决定了易感性，尽管基因和等位基因的身份仍然难以捉摸。在不同人群中的全基因组连接努力在识别含有易感基因座的区域方面取得了一定的成功，但只有一个基因座被识别出来，即calain-10。要了解导致2型糖尿病的全部基因变异，最终可能需要检查基因组中的所有基因。这当然需要对参与葡萄糖稳态的关键基因和相关途径进行全面评估。为此，我们已经确定了500个最有可能影响糖尿病风险的基因。这一组可能代表了大多数潜在的糖尿病基因。评估这些基因的贡献需要在每个基因中键入10到15个SNPs，以捕捉它们的全部单倍型多样性。这些研究是对新兴的全基因组关联研究(包括我们自己的)的必要补充，这些研究是在糖尿病易感性的背景下进行的。具体地说，我们建议：目标1.确定500例2型糖尿病候选基因的遗传变异对风险的影响；来自德克萨斯州斯塔尔县的500名墨西哥裔美国人的代表性队列；目标2.在第二组500例病例和来自德克萨斯州斯塔尔县的500名墨西哥裔美国人的队列中，测试目标1的重要发现的重复性；以及目标3.确定在途径和基因水平上导致观察到的关联的潜在分子变异。有DMA和表型可用。我们还使用Affymetrix基因芯片人类图谱100K对300例2型糖尿病患者和300名队列成员进行了全基因组分型，这是目标1的重点。在第一年，我们将重点关注100K芯片的结果，它提供了125个已识别基因的有效覆盖。在第二年到第四年，我们将通过Illumina，Inc.以每年125个基因的速度进行基因分型。基因将在生化途径的背景下进行检查，以测试一条途径中的一系列变异在病例和队列之间是不同的。基因类型将在www.diabetesgenomics.org上公布，以允许复制和应用替代分析策略。分析、复制和后续基因分型将由德克萨斯大学休斯顿健康科学中心的克雷格·L·哈尼斯博士领导的小组和格雷姆·I·贝尔博士领导的芝加哥大学分享。基因分型我们丰富的样本资源将使我们能够识别关键的糖尿病易感基因，这些基因的变异对上个世纪的环境变化是“允许的”。

DESCRIPTION (provided by applicant): Type 2 diabetes continues an unrelenting assault on health. Ample evidence implicates genetic factors in determining susceptibility although the identities of the genes and alleles have remained elusive. Genome-wide linkage efforts in diverse populations have been modestly successful in identifying regions harboring susceptibility loci, but have led to the identification of only one locus, calpain-10. Understanding the full array of genetic variation contributing to type 2 diabetes may ultimately require examination of all genes in the genome. It certainly will require comprehensive evaluation of the key genes involved in glucose homeostasis and related pathways. To this end, we have identified 500 genes most likely to influence diabetes risk. This group could represent the majority of potential diabetes genes. Evaluation of the contribution of these genes requires typing 10 to 15 SNPs in each to capture their full haplotype diversity. These studies are a necessary complement to the burgeoning genome-wide association studies (including our own) that are being performed in the context of diabetes susceptibility. Specifically, we propose: Aim 1. To determine the impact of genetic variation at 500 type 2 diabetes candidate genes on risk in 500 cases and a representative cohort of 500 Mexican Americans from Starr County, Texas; Aim 2. To test for replication of significant findings from Aim 1 in a second set of 500 cases and cohort of 500 Mexican Americans from Starr County, Texas; and Aim 3. To determine the underlying molecular variation responsible for observed associations at the pathway and gene level. DMA and phenotypes are available. We have also completed genome-wide typing using the Affymetrix GeneChip Human Mapping 100K Set on 300 of the type 2 diabetes cases and 300 cohort members that are the focus of Aim 1. In year 1 we will focus on the results from the 100K chip which provides effective coverage of 125 of the genes identified. In years 2 through 4, we will obtain genotyping through Illumina, Inc. at a rate of 125 genes per year. Genes will be examined in the context of biochemical pathways to test that the array of variation in a pathway differs between cases and the cohort. Genotypes will be posted at www.diabetesgenomics.org to permit replication and application of alternative analytic strategies. Analyses and replication and follow-up genotyping will be shared by groups at the University of Texas Health Science Center at Houston headed by Dr. Craig L. Hanis and the University of Chicago headed by Dr. Graeme I. Bell. Genotyping our extensive sample resource will permit identification of key diabetes susceptibility genes whose variation has been "permissive" to the last century's environmental changes.