We propose to examine, in a large prospective nested case-control study of 4,300 ethnically diverse postmenopausal women, the roles of two inflammatory cytokines (i.e., TNF-a and IL-6), an acute-phase reactant (i.e., C-reactive protein), three markers of endothelial activation (i.e., ICAM-l, VCAM-l, and E-selectin), and genetic variants in six related candidate genes in the development of type 2 diabetes mellitus (DM). Although accumulating data linking inflammation and endothelial dysfunction to obesity and insulin resistance suggest central roles of these biochemical markers in the etiology of type 2 DM, little prospective data are available examining their roles as predictors for future risk of type 2 DM, especially among women and minority groups. In a focused series of studies employing blood samples obtained at baseline from approximately 83,000 postmenopausal women free of cardiovascular disease or type 2 DM participating in the Women's Health Initiative Observational Study Cohort, we will determine prospectively the independent and joint contributions of the above biochemical markers in predicting future risk of type 2 DM. In parallel, we will examine genetic variants, particularly those within the coding and promoter regions, of the six specific candidate genes that directly affect inflammation/endothelial activation (including TNF, NOS3, and PPARgamma) and obesity and insulin resistance (TNF-alpha, PPARgamma, UCP2, CAPN10, and aP2). In addition, we will conduct a comprehensive evaluation of polymorphisms within several promising candidate genes of type 2 DM susceptibility using analysis of haplotype frequency with state-of-the art genotyping technology and statistical methods. Furthermore, most genetic studies of type 2 DM have come from Caucasian or American-Indian populations and limited data are available from other ethnic populations. Because previous studies have demonstrated that the susceptibility genes may vary significantly across different populations, comparison of data from different ethnic groups will improve our understanding of genetic predictors for future risk of type 2 DM. Findings from this series of comprehensive yet focused analyses could shed new light on the etiology of type 2 DM, especially among minority Americans such as Hispanic/Latinos, Blacks/Africans, and Asians/Pacific Islanders who bear a disproportionately high burden of this disease yet have been poorly studied. Knowledge gained from this proposed study may suggest new intervention strategies to lower the incidence of type 2 DM in the general population.