Studies from this project have shown that hostility is related to various measures of glucose metabolism. Furthermore, hostility is differentially related to glucose metabolism in Caucasian and African American male and female subjects. While high hostile Caucasian subjects are relatively hyperinsulinemic and insulin resistant compared to low hostile Caucasian subjects, high hostile African Americans have higher fasting glucose levels than low hostile African Americans. Furthermore, the effects of hostility on insulin resistance are more pronounced in females. We have also shown that polymorphisms of two genes that are critically involved in regulation of serotonergic function throughout the body are associated with increased fasting glucose and insulin in subjects with high 5HIAA in cerebral spinal fluid. To further explore these findings, this project will assess measures of glucose metabolism (fasting glucose and insulin, glucose tolerance, HbA1C, and insulin sensitivity) as well as other variables related to the metabolic syndrome (lipids, BMI, central adiposity and blood pressure) in a sample comprised of a minimum of 400 probands (half African American and half Caucasian, half men and half women, and half scoring in the top and half in the bottom 20% on a valid, measure of hostility that predicts CVD and has heritability estimates of 40-55%) and at least one sibling for every proband, to make a total sample of 800-1200 subjects who will participate in the protocol of this project. Our first goal will be to evaluate a minimum of 4 l candidate genes/loci that act either directly or in interaction with environmental factors, or as a function of linkage disequilibrium with other sites or membership in haplotypes, to influence expression of hostility and the individual components of the metabolic syndrome as well as their tendency to cluster. Furthermore, in collaboration with Projects 1 and 3, we will identify candidate genes/loci that account for the clustering of these metabolic abnormalities with cardiovascular, neuroendocrine, platelet function and inflammatory markers assessed in those Projects. Such knowledge could increase understanding of the contribution of gene-environment interactions to pathogenic mechanisms whereby psychosocial and biobehavioral risk factors increase CVD risk, thereby helping to identify highly susceptible persons who might be targets for primary prevention trials.
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