Genetics of Type 2 Diabetes in Starr County, Texas

描述（由申请人提供）：2型糖尿病继续对健康造成无情的攻击。尽管基因和等位基因的身份仍然难以捉摸，但充分的证据表明遗传因素在决定易感性。在不同人群中进行的全基因组连锁研究在确定易感位点区域方面取得了一定的成功，但只确定了一个位点，即calpain-10。了解导致2型糖尿病的全部遗传变异可能最终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和相关途径的关键基因进行全面的评估。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。这一群体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分型10到15个snp，以获得它们完整的单倍型多样性。这些研究是对新兴的全基因组关联研究（包括我们自己的研究）的必要补充，这些研究正在糖尿病易感性的背景下进行。具体而言，我们提出：目标1。确定500个2型糖尿病候选基因的遗传变异对500例病例和500名来自德克萨斯州斯塔尔县的墨西哥裔美国人的代表性队列的风险的影响；目标2。在第二组来自德克萨斯州斯塔尔县的500例病例和500名墨西哥裔美国人队列中测试Aim 1的重要发现的重复性；和Aim 3。确定在通路和基因水平上观察到的相关的潜在分子变异。DMA和表型是可用的。我们还使用Affymetrix基因芯片人类图谱100K集完成了300例2型糖尿病患者和300名队列成员的全基因组分型，这是Aim 1的重点。在第一年，我们将重点关注100K芯片的结果，该芯片提供了125个已识别基因的有效覆盖。在第2年至第4年，我们将以每年125个基因的速度通过Illumina公司进行基因分型。基因将在生化途径的背景下进行检查，以测试途径中的变异阵列在病例和队列之间是不同的。基因型将发布在www.diabetesgenomics.org上，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位于休斯顿的德克萨斯大学健康科学中心（由Craig L. Hanis博士领导）和芝加哥大学（由Graeme I. Bell博士领导）的研究小组共享。基因分型我们广泛的样本资源将允许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.