Gene-by-Smoking Interaction and Risk of Atherosclerosis

基因与吸烟的相互作用与动脉粥样硬化的风险

• 批准号: 6905581
• 负责人: Kari E. North
• 金额: $ 28.5万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905581
• 关键词: African American; DNA repair; artery; atherosclerosis; cardiovascular disorder risk; carotid artery; caucasian American; cerebrovascular disorders; clinical research; coronary disorder; cytochrome P450; enzyme activity; gene environment interaction; gene interaction; genetic polymorphism; genetic susceptibility; human middle age (35-64); human subject; longitudinal human study; oxidative stress; patient oriented research; single nucleotide polymorphism; smoking; tobacco abuse; toxin metabolism

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.

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有效危险因素，但个体对吸烟的易感性差异很大，可能存在基因组变异等修饰因素。参与诱变烟草烟雾化合物的激活和解毒、氧化应激和DNA损伤的几个关键酶在心脏和血管组织中表达，并代表烟草诱导病理的机制途径。这些酶中有许多具有已知功能效应的常见多态性（在人群中患病率大于或等于10%）。尽管受限于几种酶，并受到设计缺陷的阻碍，但少数研究表明，酶的激活和烟草烟雾的解毒可以改变与吸烟相关的某些心血管疾病的风险。该研究的主要目的是评估常见的基因多态性，这些基因多态性与烟草烟雾暴露相结合，可能会改变动脉粥样硬化及其临床后遗症的风险。

项目成果

Angiotensin II type 1 receptor polymorphisms and susceptibility to hypertension: a HuGE review.

血管紧张素II类型1型受体多态性和对高血压的易感性：巨大的综述。

• DOI: 10.1097/gim.0b013e3181809613
• 发表时间: 2008-08
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Mottl AK;Shoham DA;North KE
• 通讯作者: North KE