The Genetics Of Biobehavioral Risk Factors For CVD

描述(由申请人提供)： 在过去15年对该计划项目拨款的支持中，我们试图确定增加心血管疾病风险的心理社会因素，并了解通过生物行为机制调节风险增加的机制。在目前的5年支持期间，我们已经实现了我们的广泛目标：1)记录低社会经济地位人群中心血管疾病的心理社会和生物行为风险因素的聚集；2)记录早期环境对这种聚集的重要影响；以及3)记录大脑5-羟色胺能功能作为这种聚集的重要贡献者的作用。我们还发起了一项重大的新研究计划--识别5-羟色胺相关基因的多态性，作为一种新的手段，以证明5-羟色胺能机制在增加心血管疾病风险的心理社会和生物行为因素聚集中的重要性。基于目前PPG期间我们研究的每个系统中5-羟色胺转运体和单胺氧化酶A基因的多态与表型之间的广泛关联的发现，我们现在提议进行一项大规模和雄心勃勃的研究，涉及多达500名敌意先驱及其500多名兄弟姐妹，以识别影响敌意表达的遗传变异，以及在相同个体和低SES组中与敌意聚集在一起的其他心理社会和生物行为表型。项目1将寻找影响敌意、个性、心血管、神经内分泌和血小板功能的遗传变异，以及在休息和应对压力时循环中的炎症标志物。项目2将寻找影响葡萄糖代谢和代谢综合征的基因。项目3将寻找在现实世界中影响动态压力标志物的基因。五个核心将支持这些项目。这项拟议的研究代表了杜克行为医学研究中心和人类遗传学中心的研究人员之间的一项新合作，它可以识别与应激环境相互作用的基因变异，通过对损害健康的心理社会和生物行为内表型的影响来增加心血管疾病风险-从而增加对致病机制的理解，并提高能够识别可能同时进行二级和一级预防试验的高度易感人群的可能性。

DESCRIPTION (provided by applicant): For the previous 15 years of support on this program project grant, we have sought to identify psychosocial factors that increase cardiovascular disease risk and to understand the biobehavioral mechanisms whereby increased risk is mediated. During the current 5-year period of support, we have met our broad objectives to: 1) document the clustering of psychosocial and biobehavioral risk factors for CVD in persons of low socioeconomic status; 2) document the important influence of early environments on this clustering; and 3) document the role of brain serotonergic function as an important contributor to this clustering. We have also initiated a major new research initiative - identification of polymorphisms of serotonin-related genes as a new means of documenting the importance of serotonergic mechanisms in clustering of psychosocial and biobehavioral factors that increase CVD risk. Based on findings of extensive associations between polymorphisms of the serotonin transporter and monoamine oxidase A genes and phenotypes in every system we have studied during the current PPG, we propose now to undertake a large scale and ambitious study, involving up to 500 hostile probands and over 500 of their siblings, to identify genetic variants - using family-based association studies of candidate genes and loci - that influence the expression of hostility and the other psychosocial and biobehavioral enophenotypes that cluster with hostility in the same individuals and low SES groups. Project 1 will search for genetic variants that influence hostility, personality, and cardiovascular, neuroendocrine, and platelet functions, as well as circulating inflammatory markers at rest and in response to stress. Project 2 will search for genes that influence glucose metabolism and the metabolic syndrome. Project 3 will search for genes that influence ambulatory markers of stress in the real world. Five Cores will support the Projects. Representing a new collaboration between investigators in the Duke Behavioral Medicine Research Center and the Center for Human Genetics, the proposed research could identify genetic variants that interact with stressful environments to increase CVD risk via effects on healthdamaging psychosocial and biobehavioral endophenotypes - thereby increasing understanding of pathogenic mechanisms and raising the possibility of being able to identify highly susceptible persons who may be candidates for both secondary and primary prevention trials.