Genetic and Epidemiological Predictors of Glucose Homeostasis Measures

血糖稳态措施的遗传和流行病学预测因子

基本信息

批准号：
10338054
负责人：
Nicholette D. Allred
金额：
$ 64.46万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338054
关键词：
Affect African American American Architecture Asian Beta Cell Biological Biological Process Cardiovascular Diseases Case-Control Studies Cellular biology Clinical Clinical Management Collaborations Communities Complement Complex Data Data Set Defect Detection Diabetes Mellitus Diagnosis Disease Early Diagnosis Economic Burden Effectiveness Epidemiology European Evaluation Functional disorder Funding Genes Genetic Genetic Determinism Genetic Variation Genetic study Glucose Goals Heritability Hispanic Populations Human Individual Insulin Resistance Intervention Letters Linkage Disequilibrium Maps Measures Medical Care Costs Meta-Analysis Methodology Mexican Mexican Americans Minority Groups Modeling Nature Non-Insulin-Dependent Diabetes Mellitus Pattern Phenotype Physiological Population Prediabetes syndrome Prevention Public Health Recording of previous events Report (document)Research Resources Risk Sample Size Sampling South Asian Testing Translating Translations Variant blood glucose regulation case control clinical phenotype clinically relevant cohort design diabetes risk genome wide association study genome-wide high risk improved in silico indexing insight insulin secretion insulin sensitivity metabolomics molecular phenotype multi-ethnic multiple omics next generation sequencing novel rare variant resistance gene risk prediction success trait

项目摘要

Summary Insulin sensitivity and insulin secretion are traits that have a significant impact on the risk of type 2 diabetes (T2D). The over-arching goal of this proposal is to understand the pathophysiology underlying variation of these intermediate phenotypes in Mexican Americans, the largest US minority group and one at high risk of T2D. The Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium represents the largest effort to identify the genetic determinants underlying diabetes-related intermediate phenotypes (DK085175). During the previous funding period, genome-wide association studies (GWAS) focused on common genetic variation identified four genome-wide significant loci underlying variation in glucose homeostasis traits which translated to the clinical endpoint, T2D. In this application, we will build upon significant prior genetic findings with integration of biological (metabolomics) and analytical (hierarchical clustering and interaction analysis) approaches to further refine insulin resistance and insulin secretion phenotypes and explore their biological basis. Aim 1 will develop a novel methodology using existing GWAS and metabolomics data to impute genetically regulated metabolites (GReM) and test their association with measures of glucose homeostasis in the GUARDIAN Consortium. Aim 2 will refine known and novel variants associated with T2D and related phenotypes through hierarchical clustering and perform interaction analyses which exploit the bimodal nature of T2D to identify additional insulin resistance loci. Aim 3 will identify genetic determinants of dynamic measures of glucose homeostasis in diverse human populations and translate these loci to T2D. The unique strengths of this proposal include detailed phenotypes for glucose homeostasis that have not been extensively examined in the GWAS setting, a focus on the Mexican American population, and our long-standing, highly productive collaborative team. This project has great public health significance as it is focused on increasing our biological understanding and resultant mechanisms for the prevention of T2D using pre-diabetic measures of glucose homeostasis.

概括胰岛素敏感性和胰岛素分泌是对 2 型糖尿病风险有重大影响的特征（T2D）。该提案的首要目标是了解潜在变异的病理生理学墨西哥裔美国人中存在这些中间表型，墨西哥裔美国人是美国最大的少数群体，也是罹患该病的高风险人群 T2D。西班牙裔糖尿病遗传学 (GUARDIAN) 联盟代表了最大的努力确定糖尿病相关中间表型的遗传决定因素 (DK085175)。期间之前的资助期间，全基因组关联研究（GWAS）重点关注常见的遗传变异确定了四个全基因组显着基因座，这些基因座是葡萄糖稳态特征变异的基础，这些基因座翻译达到临床终点 T2D。在此应用中，我们将建立在重要的先前遗传发现的基础上生物学（代谢组学）和分析（层次聚类和相互作用分析）的整合进一步完善胰岛素抵抗和胰岛素分泌表型并探索其生物学特性的方法基础。目标 1 将开发一种新的方法，利用现有的 GWAS 和代谢组学数据来估算基因调节代谢物（GReM）并测试它们与葡萄糖稳态测量的关联守护者联盟。目标 2 将完善与 T2D 及相关疾病相关的已知和新颖变异通过层次聚类分析表型，并利用双峰性质进行相互作用分析 T2D 以确定其他胰岛素抵抗位点。目标 3 将确定动态的遗传决定因素测量不同人群中的葡萄糖稳态，并将这些基因座转化为 T2D。独特的该提案的优点包括尚未广泛研究的葡萄糖稳态的详细表型在 GWAS 环境中进行了检查，重点关注墨西哥裔美国人，以及我们长期以来高度重视的富有成效的协作团队。该项目具有重大公共卫生意义，因为它的重点是增加我们对使用糖尿病前期措施预防 T2D 的生物学理解和由此产生的机制葡萄糖稳态。