Gene-by-Smoking Interaction and Risk of Atherosclerosis

描述(由申请人提供)：虽然吸烟是动脉粥样硬化性血管疾病的一个公认的和强有力的危险因素，但个体对吸烟的易感性差异很大，这表明基因变异等修饰因素。几种关键的酶参与了诱变烟草烟雾化合物的激活和解毒、氧化应激和DNA损伤，在心脏和血管组织中表达，代表了烟草诱导的病理机制。这些酶中的许多都有共同的多态(在人群中的流行率大于或等于10%)，具有已知的功能效应。尽管仅限于少数几种酶，并受到设计缺陷的阻碍，但少数研究表明，烟草烟雾的酶激活和解毒可以改变与吸烟相关的某些心血管后果的风险。这项拟议研究的主要目的是评估常见的基因多态，结合烟草烟雾暴露，可能会改变动脉粥样硬化及其临床后遗症的风险。 根据其流行率和功能意义、在相关组织中的表达、先前研究中的评估和生物可信度，19个参与激活、解毒、氧化应激和DNA修复途径的基因中的平均6个多态性将被作为社区动脉粥样硬化风险(ARIC)研究的辅助研究进行评估。自1987-89年来，这项由15,792名男性和女性组成的双族队列得到了积极的跟进(随访完成率为96%)，其中5个终点将以病例队列/病例对照的方式进行研究，这些终点量化了亚临床动脉粥样硬化和已证实的临床动脉粥样硬化事件：冠心病、颈动脉粥样硬化、外周动脉疾病、偶发中风和核磁共振检测到的脑梗塞。这项拟议的研究旨在研究DNA序列多态如何促进或抑制吸烟的致动脉粥样硬化效应和临床事件的风险，并就遗传变异在环境侮辱和毒物反应中的作用提供新的知识。预计这一发现将具有临床和公共卫生意义。

DESCRIPTION (provided by applicant): While cigarette smoking is a well-established and potent risk factor for atherosclerotic vascular disease, individual susceptibility to smoking varies considerably, suggesting modifiers such as genomic variation. Several key enzymes involved in the activation and detoxification of mutagenic tobacco smoke compounds, oxidative stress, and DNA damage are expressed in the tissues of the heart and vasculature and represent mechanistic pathways for tobacco-induced pathology. Many of these enzymes have common polymorphisms (greater than or equal too 10% prevalence in the population) with known functional effects. Although restricted to a few enzymes and hampered by shortcomings in design, a small number of studies have suggested that enzymatic activation and detoxification of tobacco smoke modifies the risk of certain cardiovascular outcomes associated with cigarette smoking. The main goal of the proposed study is to evaluate common genetic polymorphisms that, in combination with exposure to tobacco smoke, may modify the risk of atherosclerosis and its clinical sequelae. An average of six polymorphisms, selected on the basis of their prevalence and functional significance, expression in relevant tissues, evaluation in previous studies and biologic plausibility, within 19 genes involved in activation, detoxification, oxidative stress, and DNA repair pathways will be evaluated as an ancillary study to the Atherosclerosis Risk in Communities (ARIC) study. In this well-characterized, bi-ethnic cohort of 15,792 men and women under active follow-up since 1987-89 (completeness of follow-up 96%), five endpoints quantifying subclinical atherosclerosis and validated clinical atherosclerotic events will be studied in case-cohort/case-control mode: incident coronary heart disease, carotid atherosclerosis, peripheral arterial disease, incident stroke, and MRI-detected cerebral infarcts. The proposed investigation is well designed to study how DNA sequence polymorphisms can promote or inhibit the atherogenic effects of smoking and the risk of clinical events, and to contribute new knowledge on the role of genetic variation in the response to environmental insults and toxicants. The findings are expected to be of clinical and public health significance.