Type 2 diabetes mellitus and its atherosclerotic complications impose a substantial burden on health of Americans in general and on African Americans in particular. Recent discoveries in molecular genetics have lead to the identification of functional variations in several candidate genes for susceptibility to obesity, insulin resistance, and/or diabetes. These include genes which code for beta-2and beta-3 adrenergic receptors, insulin receptor substrate 1, fatty acid binding protein 2, frataxin, and leptin receptor. If their role as novel susceptibility factors is confirmed, these variants promise to illuminate the pathophysiologic basis of diabetes and diabetes related cardiovascular diseases, accelerate the development of chemopreventive agents, and facilitate the conduct of prevention trials by marking individuals at high risk. Unfortunately many previous association studies of these mutations in human populations have been limited by small, selected study samples; by limited cross-sectional data on behavioral factors and on cardiovascular risk phenotype; and by paucity of data on African Americans. The investigators, therefore, propose to conduct an epidemiologic study of functional variants in 10 candidate genes for susceptibility to type 2 diabetes, obesity, and insulin resistance. The main objective will be to detect modest effects consistent with polygenic nature of diabetes but with better sensitivity and precision than previous association and linkage studies. The study sample will a community based cohort of 3,250 African Americans and 3,250 Whites aged 45 to 64 who are participants in the ongoing Atherosclerosis Risk in Communities (ARIC) study. Supported by NHLBI the ARIC study has assembled an extensive data base including behavioral assessment (e.g. diet and physical activity), anthropometry, laboratory blood tests (e.g. oral glucose tolerance test and serum lipids), and carotid ultrasonography as well as clinical events and mortality. Using race specific case-control, cross-sectional, and longitudinal analyses the investigators will determine if these putative diabetes alleles are associated with incident and prevalent diabetes, with obesity and weight gain, with hyperinsulinemia in non-diabetic individuals with the presence of an adverse cardiovascular risk factor profile, and with atherosclerosis progression and cardiovascular disease incidence over 12 years of follow up. The investigators will assess how behavioral and environmental factors such as obesity, diet, and physical activity, influence the expression of genetically conferred risk. Strength of this proposal include the close collaboration between clinical, epidemiologic, and laboratory researchers, a wealth of prospectively collected data from an NIH sponsored study, and a sample size large enough to detect modest gene effects and to investigate gene-gene and gene-environmental interactions. Most important, this study will provide unique information on the expression of diabetes susceptibility genes in the general population and possibly suggest genetic explanations for the excess prevalence of type 2 diabetes and obesity in African Americans.
