Genetics of Beta Cell Failure in Mexican Americans

描述(申请人提供)：我们研究的长期目标是了解在相对年轻的拉美裔美国人中导致2型糖尿病(T2D)的机制，以便开发更好的预测、预防和早期治疗的方法。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的头五年里，我们对1235名有妊娠期糖尿病(GDM)先证者或妊娠期糖耐量正常的墨西哥裔美国家庭的个体进行了口服(OGTT)和静脉(IvGTT)葡萄糖耐量试验和DEXA身体成分测试。在另一组有妊娠期糖尿病病史的西班牙裔女性中，我们发现T2D是在慢性胰岛素抵抗的背景下，随着时间的推移，胰腺b细胞功能的进行性丧失所致。我们和其他人测试的b细胞功能的横截面差异与假定的T2D基因的相关性，充其量只是更重要的纵向变化的替代。支持这一建议的主要假设是一个或多个T2D基因影响胰岛素抵抗b细胞代偿的变化率。我们从对HNF4a的初步研究中为我们的假设提供了强有力的证据。我们将实现三个目标，以更充分地检验我们的假设。首先，我们将从Betagene样本中随机招募400名个体，并在他们的基线检查后3-5年进行重新表型。它们将是我们基于b细胞薪酬变化进行关联研究的主要资源。其次，我们已经在对T2D和相关数量性状的20个基因的整个Betagene队列进行基因分型。当T2D和T2D相关表型被发现时，我们将对纵向队列中的相关新基因进行基因分型，并为一组祖先信息的标记评估种群亚结构。第三，我们将分析数据，以测试T2D和T2D相关表型的变异与b细胞代偿的变异率之间的关联。我们还将测试遗传效应和b细胞环境因素(如肥胖、胰岛素抵抗、饮食、体力活动)对b细胞补偿变化率的影响。我们的结果将提供关于导致拉美裔美国年轻人T2D的主要生理异常的遗传影响的独特信息。它们还将提供关于遗传变异与肥胖、胰岛素抵抗和b细胞功能之间相互作用的独特信息。这些信息将有助于指导基因对糖尿病的作用机制研究。它还将为糖尿病预测、预防和早期治疗的新的临床方法提供基础。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。这一结果将有助于指导2型糖尿病发病机制的基础研究。这一结果还将有助于指导开发新的方法来预测、预防和早期治疗这一高危民族的2型糖尿病。

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.