Insulin sensitivity, metabolic clearance rate of insulin (MCRI), and insulin secretion are traits that all have a significant impact on the risk of type 2 diabetes (T2DM). The over-arching goal of this proposal is to identify the genetic variants underlying variation in insulin resistance, MCRI, and insulin secretion in Hispanic Americans, the largest US minority group and one at high risk of T2DM. In the IRAS Family Study (funded for two five-year cycles by NHLBI), we have recruited a large Hispanic cohort and obtained detailed and novel phenotypic measures of glucose homeostasis, obesity and other traits. We have identified a substantial genetic contribution and potential genomic locations to many of these measures through heritability analysis, linkage analysis, candidate gene association studies and, most recently, a pilot genome-wide association scan (GWAS). In this renewal application, we propose to extend these findings by developing a consortium of studies that have similar measures of these critically important phenotypes related to T2DM risk and access to DNA samples in Hispanic cohorts. The GUARDIAN Consortium (Genetics Underlying Diabetes in Hispanics) has the following goals: (1) to perform a GWAS to detect loci underlying variation in glucose homeostasis traits in a multi-cohort pedigree-based set of 4685 Hispanics;(2) to translate/extend these findings to the relevant clinical disease, T2DM, by testing for association in a set of ~3500 T2DM cases and ~5500 controls;and (3) to sequence up to 12 genetic loci from our GWAS in order to identify specific variants contributing to variation in glucose homeostasis traits and susceptibility to T2DM. The unique strengths of the proposed study include the highly detailed phenotypes of glucose homeostasis in the discovery sample that have not been previously examined in the GWAS setting, the large population size available with these measures in a Hispanic cohort, and our long-standing, highly productive collaborative team. This project has great public health significance as it is focused on increasing our understanding and mechanisms for the prevention of T2DM using pre-diabetic measures of glucose homeostasis.
This project proposes to evaluate the genetic basis of factors that predispose to type 2 diabetes, namely insulin resistance, metabolic clearance rate of insulin, and insulin secretion, in a US minority population, Hispanics. The public health significance of this project is its contribution toward an improved understanding of type 2 diabetes, a highly prevalent condition.
|Hellwege, Jacklyn N; Palmer, Nicholette D; Dimitrov, Latchezar et al. (2017) Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans. J Hum Genet 62:175-184|
|Graff, Mariaelisa; Emery, Leslie S; Justice, Anne E et al. (2017) Genetic architecture of lipid traits in the Hispanic community health study/study of Latinos. Lipids Health Dis 16:200|
|Wood, Andrew R; Jonsson, Anna; Jackson, Anne U et al. (2017) A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants. Diabetes 66:2296-2309|
|Palmer, Nicholette D; Wagenknecht, Lynne E; Langefeld, Carl D et al. (2016) Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium. Diabetes 65:2072-80|
|Knowles, Joshua W; Xie, Weijia; Zhang, Zhongyang et al. (2015) Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. J Clin Invest 125:1739-51|
|Gao, Chuan; Wang, Nan; Guo, Xiuqing et al. (2015) A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS). PLoS One 10:e0134649|
|Sharma, Poonam R; Mackey, Aaron J; Dejene, Eden A et al. (2015) An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes. Endocrinology 156:3147-56|
|Palmer, Nicholette D; Goodarzi, Mark O; Langefeld, Carl D et al. (2015) Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium. Diabetes 64:1853-66|
|Palmer, Nicholette D; Stevens, Robert D; Antinozzi, Peter A et al. (2015) Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study. J Clin Endocrinol Metab 100:E463-8|
|Goodarzi, Mark O; Langefeld, Carl D; Xiang, Anny H et al. (2014) Insulin sensitivity and insulin clearance are heritable and have strong genetic correlation in Mexican Americans. Obesity (Silver Spring) 22:1157-64|
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