Obesity is increasing in prevalence in Western societies, and it represents a major health concern because it increases the risk of cardiovascular disease, metabolic disorders and some forms of cancer. It is estimated that 40% to 70% of the variability in body weight is genetically mediated. A number of genes have been studied as candidate genes for obesity. In the proposed analysis of the Women's Ischemic Syndrome Evaluation Study (WISE) database, we will test the hypothesis that the beta- adrenergic receptor (betaAR) genes and certain G protein genes are associated obesity. Specifically, we will be studying the association between obesity and genes of the beta1AR (ADRB1), the beta2AR (ADRB2), the beta3AR (ADRB3), the Gs protein alpha subunit (GNAS1) (all three betaARs couple with Gs) and the G protein beta3 subunit (GNB3) (a component of Gi, to which beta3ARs couple). We will also examine the multivariate contributions to obesity of genotype, demographic (e.g., age, region) and environmental (e.g., exercise, childbirth history) factors and their possible interactions. Data for the proposed analysis will derive from the database of the WISE study, a four center NHLBI-funded study of ischemic heart disease in women. Genotypes will be assessed by a high through-put genetic bit analysis method. Analyses on approximately 590 white women and 130 black women will be performed separately, and will include multiple regression analysis to test for impact of the various genes, and various demographic and behavioral factors on body mass index. The proposed analyses are important and novel because they will: a) provide the first information on the relationship between ADRB1 and GNAS1 and obesity, b) provide the first information on the ADRB2 and obesity when assessed by haplotype, c) provide information on potential additive or synergistic effects of the genes under study with respect to obesity, d) for some of the genes, provide the first data on the gene-obesity associations in blacks, e) assess the gene-obesity association with respect to certain environmental/behavioral factors such as physical activity and previous childbirth, and f) utilize a state-of-the-art high throughput method for genetic analysis. The information generated from this study should help identify candidate genes that are worthy of further, extensive investigation. Knowledge about genes that are associated with obesity is important as this information may aid in the drug discovery process for anti-obesity drugs. Additionally, genotyping individuals early in age may help to identify those at increased risk of obesity prior to them becoming obese so that they may take appropriate preventive measures.
