GENETIC, HOSTILITY, PERSONALITY & BIOMARKERS OF STRESS

这个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)的心理社会和生物行为危险因素表达中的作用。我们建议找出候选基因和染色体的变异，这些变异与敌意的内表型、人格维度、其他心理社会风险因素、健康行为、静息和应激时的心血管和神经内分泌功能、静息和应激时的血小板激活和5-羟色胺转运体功能的指数有关。 静息和应对压力时的循环炎症标志物，以及所有这些特征聚集在相同的个人和低社会经济群体中的趋势。我们将招募400名先证者(一半是非洲裔美国人，一半是高加索人，一半是男性，一半是女性，根据预测心血管疾病的有效敌意衡量标准，一半得分在顶部，一半在底部20%，遗传率估计为40%-55%)，每个先证者至少有一个兄弟姐妹，以对800-1200名参与该项目方案的受试者以及尽可能多的父母进行基因分型，并只完成纸笔测试。我们将为至少41个候选基因/基因座的所有先证者、同胞和父母进行基于家庭的关联研究，以确定候选基因/基因座的多态，这些基因/基因座直接或与环境因素相互作用，或作为 与单倍型中其他位点或成员的连锁不平衡、敌意的表达、与敌意相关的人格维度、其他心理社会风险因素、健康行为、静息和精神应激反应中的心血管、神经内分泌、血小板和炎症标记物，以及这些内表型聚集的趋势。作为第一个包括足够数量的男性和女性以及非裔美国人和高加索人的大规模研究，这些人的候选基因/基因座的基因分型与已知增加心血管疾病风险的心理社会和生物行为内表型及其聚集性的相关性进行了检查，拟议的研究有可能确定增加心血管疾病风险的基因-环境相互作用。这些知识可以增加对基因-环境相互作用对致病机制的贡献的理解，从而 心理社会和生物行为风险因素增加了心血管疾病的风险，从而有助于识别可能成为初级预防试验目标的高度易感人群。

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.