Genetics of Beta Cell Failure in Mexican Americans

描述（由申请人提供）：我们研究的长期目标是了解导致相对年轻的西班牙裔美国人2型糖尿病（T2D）的机制，以便开发更好的预测、预防和早期治疗方法。BetaGene研究的具体目标是确定易患T2D的基因，并了解这些基因如何促进糖尿病的发展。在BetaGene的前5年，我们对1235名患有妊娠期糖尿病（GDM）或妊娠期正常糖耐量的墨西哥裔美国家庭的先证个体进行了口服（oGTT）和静脉注射（ivGTT）葡萄糖耐量试验和DEXA体成分试验。在另一组既往患有GDM的西班牙裔女性中，我们发现T2D是由于多年来慢性胰岛素抵抗背景下胰腺b细胞功能的进行性丧失引起的。我们和其他人已经测试了与假定的T2D基因相关的b细胞功能的横断面差异，最多只能替代更重要的纵向变化。这一提议的主要假设是一个或多个T2D基因影响b细胞对胰岛素抵抗的代偿率。我们从HNF4A的初步研究中为我们的假设提供了强有力的证据。为了更充分地检验我们的假设，我们将实现三个目标。首先，我们将在基线检查3-5年后从BetaGene样本中随机招募400名个体并重新进行表型分析。它们将是我们基于b细胞代偿变化的关联研究的主要资源。其次，我们已经对整个BetaGene队列的20个T2D基因和相关数量性状进行了基因分型。我们将对纵向队列进行基因分型，以发现T2D和T2D相关表型的相关新基因，并对一组祖先信息标记进行基因分型，以评估群体亚结构。第三，我们将分析数据，以测试T2D和T2D相关表型的变异与b细胞代偿变化率之间的关联。我们还将测试遗传效应与b细胞环境方面（如肥胖、胰岛素抵抗、饮食、体育活动）对b细胞代偿变化率的相互作用。我们的研究结果将为西班牙裔美国年轻人中导致T2D的主要生理异常的遗传影响提供独特的信息。它们还将为遗传变异与肥胖、胰岛素抵抗和b细胞功能之间的相互作用提供独特的信息。这些信息将有助于指导基因对糖尿病的作用机制研究。这也将为糖尿病的预测、预防和早期治疗提供新的临床方法基础。公共卫生相关性：该项目旨在确定糖尿病风险基因如何影响导致墨西哥裔美国人2型糖尿病的主要异常。该结果将有助于指导2型糖尿病发病机制的基础研究。研究结果也将有助于指导新方法的发展，以预测，预防和早期治疗2型糖尿病在这一高危民族。

DESCRIPTION (provided by applicant): The long-term objective of our research is to understand the mechanisms that cause type 2 diabetes (T2D) in relatively young Hispanic Americans in order to develop better approaches to prediction, prevention and early treatment. The specific objective of the BetaGene Study is to identify genes that predispose to T2D and understand how those genes contribute to development of diabetes. In the first five years of BetaGene, we performed oral (oGTT) and intravenous (ivGTT) glucose tolerance tests and body composition by DEXA on 1235 individuals from Mexican American families with probands who had either gestational diabetes (GDM) or normal glucose tolerance during pregnancy. In a separate cohort of Hispanic women with prior GDM, we have shown that T2D results from a progressive loss of pancreatic b-cell function that occurs over the course of years on a background of chronic insulin resistance. The cross-sectional differences in b-cell function that we and others have tested for association with putative T2D genes are, at best, surrogates for the more important longitudinal changes. The primary hypothesis underlying this proposal is that one or more T2D genes influence rates of change in b-cell compensation for insulin resistance. We provide strong evidence for our hypothesis from preliminary studies of HNF4A. We will achieve three aims to test our hypothesis more fully. First, we will recruit and re-phenotype a random longitudinal cohort of 400 individuals from the BetaGene sample 3-5 years after their baseline exams. They will be our primary resource for association studies based on changes in b-cell compensation. Second, we are already genotyping the entire BetaGene cohort for 20 genes for T2D and related quantitative traits. We will genotype the longitudinal cohort for relevant new genes underlying T2D and T2D-related phenotypes as they are discovered and for a panel of ancestrally informative markers to assess population substructure. Third, we will analyze data to test for association between variants underlying T2D and T2D-related phenotypes and rates of change in b-cell compensation. We will also test for interactions between genetic effects and aspects of the b-cell environment (e.g., obesity, insulin resistance, diet, physical activity) on rates of change in b-cell compensation. Our results will provide unique information about genetic influences on the primary physiological abnormality that causes T2D in young Hispanic Americans. They will also provide unique information on the interplay among genetic variation and obesity, insulin resistance and b-cell function. The information will help guide mechanistic studies of the genetic contribution to diabetes. It will also provide a basis for new clinical approaches to diabetes prediction, prevention and early treatment. PUBLIC HEALTH RELEVANCE: This project is designed to determine how diabetes risk genes affect the major abnormalities that lead to type 2 diabetes in Mexican Americans. The results will be useful in guiding basic studies into the mechanisms of type 2 diabetes. The results will also help to guide the development of new approaches to the prediction, prevention and early treatment of type 2 diabetes in this high-risk ethnic group.