Gene-environment interaction in complex disease

描述(申请人提供)：心血管疾病(CVD)是当今工业化国家的头号死因，是一种复杂的疾病，具有多因素的病因，涉及许多遗传和环境因素。旨在减少心血管疾病风险和发生的公共卫生预防计划通常侧重于可改变的环境和行为，如饮食和体力活动，结果因个人而异。这种对心血管疾病干预反应的异质性至少在一定程度上源于遗传。虽然已经确定了一些似乎影响心血管疾病发展的候选基因，但人们对这些遗传效应在人口统计(如种族和性别)和环境(如饮食和锻炼)背景下如何变化知之甚少；因此，确定基因和环境如何相互作用产生心血管疾病是至关重要的。这项研究的目的是在社区动脉粥样硬化风险(ARIC)研究的11,625名非洲裔美国人和高加索人男性和女性的基于人群的样本中，表征87个生物和位置候选基因的环境依赖效应。根据确认的功能重要性、与心血管疾病或其危险因素的一致关联来选择候选基因座，或者在全基因组连锁扫描中确定为位置候选基因。环境背景将侧重于饮食措施(例如，总千卡数、关键分数、酒精摄入量)、肥胖、体力活动指标(运动、休闲和工作指数)、吸烟和更年期状态/激素使用(仅限女性)。结果变量将包括量化风险因素的测量(例如，总胆固醇、体重指数、血压)、亚临床疾病(颈动脉壁厚度)和临床疾病(冠心病和中风的发生率)。现有的DNA样本将用于候选基因座的基因分型，不需要与研究参与者进一步接触。ARIC队列由于其庞大的规模和丰富的环境和生理措施，提供了一个理想、及时和有效的机会来评估可改变的环境对可能影响心血管疾病风险和疾病结局的遗传变异的影响，最终目标是建立更有效的心血管疾病治疗和预防计划。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD), the number one cause of death in industrialized countries today is a complex disease with a multifactorial etiology involving many genetic and environmental factors. Public health prevention programs designed to reduce the risk and occurrence of CVD commonly focus on modifiable environments and behaviors such as diet and physical activity, with varied results among individuals. This heterogeneity in response to CVD interventions is at least in part of genetic origin. Although a number of candidate genes have been identified which appear to influence the development of CVD, little is known about how these genetic effects may vary within demographic (e.g., race and gender) and environmental (e.g., diet and exercise) contexts; thus, it is of utmost importance to determine how genes and environments interact to produce CVD. The purpose of this study is to characterize the environment-dependent effects of 87 biologic and positional candidate genes in a population-based sample of 11,625 African-American and Caucasian men and women from the Atherosclerosis Risk in Communities (ARIC) study. Candidate loci were selected based on confirmed functional significance, consistent association with CVD or its risk factors, and or identified as positional candidates in genome-wide linkage scans. Environmental contexts will focus on dietary measures (e.g., total kcals, Keys score, alcohol intake), obesity, measures of physical activity (sport, leisure, and work indices), smoking, and menopause status/hormone use (women only). Outcome variables will include measures of quantitative risk factors (e.g., total cholesterol, BMI, blood pressure), subclinical disease (carotid wall thickness), and clinical disease (incident CHD and stroke). Existing DNA samples will be used for genotyping of candidate loci, and no further contact with study participants will be necessary. The ARIC cohort, because of its large size and wealth of environmental and physiological measures, provides an ideal, timely, and efficient opportunity to evaluate the effects of modifiable environments on genetic variation which may influence CVD risk and disease outcomes with the ultimate goal of establishing more efficacious programs for the treatment and prevention of CVD.