Identification and Replication of Type 2 Diabetes Genes in Mexican Americans

描述（由申请人提供）：基因组以令人难以置信的速度变得触手可及。对2型糖尿病进行了不少于12项全基因组关联研究，在最近的欧洲血统人群中发现了至少18种可重复相关的变异。然而，在其他人群中，特定变异的复制并不一致，尽管基因本身经常显示出关联。有趣的是，这18种变异/基因似乎并没有通过共同的代谢途径相互关联，也没有与之前所理解的与葡萄糖稳态的联系密切相关。每一种都值得深入研究，以更深入、更广泛地了解它们的变异和功能。即使有了这18个基因，我们对任何人群中2型糖尿病的遗传基础的全面了解仍然远远不够。欧洲人口的成功表明，向其他种族群体的扩展肯定会发现其他基因。这些努力将通过适当组合来自多个组的数据和组内仔细的测试得到加强。我们开发的资源使墨西哥裔美国人2型糖尿病的初始全基因组关联研究和第二个更大的遗传标记研究目前正在遗传疾病研究中心（CIDR）使用Affymetrix全基因组人类SNP阵列6.0进行分型。对这些数据的分析和后续跟进，以及为其他种族群体带来类似资源和分析专业知识的研究骨干，将加速对2型糖尿病遗传基础的识别、复制和功能理解。我们建议成为NIDDK“2型糖尿病基因的多种族研究”（RFA-DK-09-004）的一部分，并：目标1：全面评估来自德克萨斯州斯塔尔县的墨西哥裔美国人中与2型糖尿病风险、并发症和相关定量表型可重复相关的所有snp附近的遗传变异；目标2：确定墨西哥裔美国人2型糖尿病的新遗传风险因素，目标3：通过深度重测序和利用网络理论和进化背景的分析来区分因果多态性。这些研究将对导致2型糖尿病的机制产生实质性的见解，并使我们更接近于了解减缓或预防其发病所需的知识。

DESCRIPTION (provided by applicant): With incredible rapidity the genome has become accessible. No fewer than 12 genome wide association studies have been performed for type 2 diabetes leading to the identification of at least 18 variants reproducibly associated in populations of recent European descent. Replication of specific variants in other population groups, however, has not been as consistent though the genes themselves often show associations. Interestingly, these 18 variants/genes do not seem to be related to each other through common metabolic pathways nor are most associated with previously understood connections to glucose homeostasis. Each merits intense investigation to develop deeper and broader understanding of their variation and function. Even with these 18 genes, we remain far short of a comprehensive understanding of the genetic underpinnings of type 2 diabetes in any population. The success in European populations indicates that extension to other ethnic groups will assuredly identify other genes. These efforts will be enhanced through appropriate combinations of data from multiple groups and careful testing within groups. The resources we have developed enabled an initial genome wide association study of type 2 diabetes among Mexican Americans and a second much larger such study with genetic markers currently being typed at the Center for Inherited Disease Research (CIDR) using the Affymetrix Genome-Wide Human SNP Array 6.0. The analyses and follow-up of these data in conjunction with a cadre of investigators bringing similar resources and analytic expertise for other ethnic groups will accelerate identification, replication and functional understanding of the genetic underpinnings of type 2 diabetes. We propose to become part of the NIDDK's "Multiethnic Study of Type 2 Diabetes Genes" (RFA-DK-09-004) and to: Aim 1: Comprehensively assess genetic variation in the vicinity of all SNPs reproducibly associated with type 2 with the risk for type 2 diabetes, its complications and related quantitative phenotypes in Mexican Americans from Starr County, Texas; Aim 2: Identify new genetic risk factors for type 2 diabetes in Mexican Americans, and Aim 3: Distinguish causal polymorphisms through deep resequencing and analyses that exploit network theory and evolutionary contexts. These studies will lead to substantial insights into the mechanisms leading to type 2 diabetes and move us much closer to the understanding required to slow its onset or prevent it. RELEVANCE: Type 2 diabetes is increasing at unprecedented rates in nearly all populations. Recent large scale studies have identified several genes that play a role in this. Using extensive data that we have developed on type 2 diabetes among Mexican Americans and joining our efforts with other groups will lead to the identification of other genes and, ultimately, strategies to slow the onset of type 2 diabetes and prevent it. Without such, we can only expect a continuing and increasing epidemic.