GENETIC, HOSTILITY, PERSONALITY & BIOMARKERS OF STRESS

该项目的总体目标是确定基因-环境相互作用在心血管疾病（CVD）的社会心理和生物行为风险因素表达中的作用。我们建议在候选基因和染色体位点中找出与敌意、人格维度、其他社会心理风险因素、健康行为、静息和应激时心血管和神经内分泌功能、静息和应激时血小板活化指数和血清素转运功能相关的变异。

The overall objective of this project is to determine the role of gene-environment interactions in the expression of psychosocial and biobehavioral risk factors for cardiovascular disease (CVD). We propose to identify variants in candidate genes and chromosomal loci that are associated with the endophenotypes of hostility, personality dimensions, other psychsocial risk factors, health behaviors, cardiovascular and neuroendocrine function at rest and in response to stress, indices of platelet activation and serotonin transporter function at rest and in response to stress, circulating inflammatory markers at rest and in response to stress, and the tendency of all these characteristics to cluster in the same individuals and low socioeconomic groups. We shall recruit 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%), 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, and as many parents as are available who will be genotyped and complete only the paper and pencil tests. We shall genotype all probands, sibs, and parents for at least 41 candidate genes/loci for family-based association studies to identify polymorphisms of candidate genes/loci that influence, either directly or in interaction with environmental factors, or as a function of linkage disequilibrium with other sites or membership in haplotypes, the expression of hostility, personality dimensions related to hostility, other psychosocial risk factors, health behaviors, and cardiovascular, neuroendocrine, platelet, and inflammatory markers at rest and in response to a Mental Stress Protocol, as well as the tendency of these endophenotypes to cluster. As the first such large scale study to include adequate numbers of men and women and African Americans and Caucasians who are genotyped for candidate genes/loci that are examined for association with psychosocial and biobehavioral endophenotypes known to increase CVD risk and their tendencies to cluster, the proposed research has the potential to identify gene-environment interactions that increase CVD risk. 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.