Insulin resistance is an important risk factor for atherosclerosis. Insulin resistance varies widely within populations and substantial evidence indicates that much of this variation can be attributed to genetic sources. Visceral adiposity, another important atherosclerosis risk factor, is strongly correlated with insulin resistance, and this trait also appears to be under substantial genetic control. The overall goals of the proposed research project are to: 1) identify the genetic determinants of insulin resistance and visceral adiposity; and 2) determine the extent to which insulin resistance, visceral adiposity, and metabolic cardiovascular disease risk factors share common genetic influences. To address these goals, we will enroll a total of 160 families of African-American and Hispanic background who are participating in the Insulin Resistance Atherosclerosis Study (IRAS), including 54 Hispanic families in our center. Approximately 1280 additional family members (432 in this center) will be recruited. Insulin resistance will be measured using the frequently sampled intravenous glucose tolerance test, and visceral adiposity will be measured using computed tomography. A panel of other metabolic cardiovascular disease risk factors will also be assessed. A panel of 370 microsatellite markers will be genotyped from DNA, and a genome-wide scan will be performed to detect chromosomal regions containing loci that influence phenotypic variation. We will then saturate the regions of linkage identified in these analyses with additional markers and will then perform linkage disequilibrium analyses in effort to localize further the putative loci. The organization of this study will be similar to that of IRAS, with three clinical centers, a coordinating center, a central laboratory and a genetics laboratory. This center will serve as one of the 3 data collection sites and will be responsible for recruiting 54 Hispanic families In addition, this center's investigators will take part in data analysis and publication. This project will contribute substantially to our understanding of the genetic determinants of insulin sensitivity, and consequently to risk of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061019-05
Application #
6607599
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Bookman, Ebony B
Project Start
1999-09-01
Project End
2004-12-31
Budget Start
2003-08-01
Budget End
2004-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$176,026
Indirect Cost
Name
University of Colorado Denver
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Gao, Chuan; Langefeld, Carl D; Ziegler, Julie T et al. (2018) Genome-Wide Study of Subcutaneous and Visceral Adipose Tissue Reveals Novel Sex-Specific Adiposity Loci in Mexican Americans. Obesity (Silver Spring) 26:202-212
Gao, Chuan; Tabb, Keri L; Dimitrov, Latchezar M et al. (2018) Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS). Sci Rep 8:5603
Hong, Jaeyoung; Hatchell, Kathryn E; Bradfield, Jonathan P et al. (2018) Transethnic Evaluation Identifies Low-Frequency Loci Associated With 25-Hydroxyvitamin D Concentrations. J Clin Endocrinol Metab 103:1380-1392
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
Lee, C Christine; Young, Kendra A; Norris, Jill M et al. (2017) Association of Directly Measured Plasma Free 25(OH)D With Insulin Sensitivity and Secretion: The IRAS Family Study. J Clin Endocrinol Metab 102:2781-2788
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
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

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