The Genetics Of Biobehavioral Risk Factors For CVD

描述（由申请人提供）： 在过去的15年里，我们一直致力于确定增加心血管疾病风险的社会心理因素，并了解介导风险增加的生物行为机制。在当前的5年支持期内，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; 3）记录大脑神经递质功能作为这种聚集的重要贡献者的作用。我们还启动了一项重大的新研究计划--鉴定降钙素相关基因的多态性，作为记录降钙素能机制在增加CVD风险的心理社会和生物行为因素聚集中的重要性的新手段。基于我们在当前PPG期间研究的每个系统中5-羟色胺转运体和单胺氧化酶A基因多态性与表型之间的广泛关联的发现，我们现在建议进行一项大规模和雄心勃勃的研究，涉及多达500名敌对先证者及其500多名兄弟姐妹，识别遗传变异-使用基于家族的候选基因和位点关联研究-影响敌意表达的其他心理社会和生物行为表型，这些表型与敌意聚集在同一个区域，个人和低社会地位群体。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的循环炎症标志物。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将在真实的世界中寻找影响压力的非卧床标志物的基因。五个核心将支持这些项目。这是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，拟议的研究可以确定与压力环境相互作用的遗传变异，通过对损害健康的心理社会和生物行为内在表型的影响来增加心血管疾病的风险-从而增加了对致病机制的理解，并提高了能够识别高度易感者的可能性，二级和一级预防试验的候选人。

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.