Genome-Wide Associations Environmental Interactions in the Lung Health Study

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是一种引起重大公共卫生问题的复杂疾病，是全球第四大死亡原因，预计到2020年发病率和死亡率将恶化。吸烟是慢性阻塞性肺疾病发展的主要环境风险因素；然而，只有10%-20%的吸烟者出现症状疾病。动物和人类研究都支持遗传因素对吸烟行为及其相关结果的作用，包括肺功能和COPD的其他表现，但只有一小部分潜在的原因基因被识别出来。肺健康研究(LHS)是一项为期14.5年的多中心随机临床试验，旨在确定吸烟干预计划和吸入性支气管扩张剂的使用是否可以减缓肺功能下降的速度或改变COPD死亡率，它是世界上最大的COPD队列之一(N=5887)。作为之前NHLBI资助的研究的一部分，我们开发了一个DNA库，包括4,800名LHS参与者。我们计划在这个特征良好的队列中对COPD和相关的数量性状进行全基因组关联研究(Gwas)，并使用现有的Gwas数据集来验证我们的发现。由于我们还假设某些基因可能导致尼古丁成瘾，从而导致烟草使用(COPD中最强烈的环境风险因素)，我们将测试遗传标记和这一结果之间的关联，并将类似地验证这些发现，并测试基因与环境的相互作用。我们应用程序的一个主要优势是与温哥华James Hogg iCAPTURE心血管和肺研究中心以及明尼苏达大学LHS数据协调中心的同事合作。其他与在相关数据集中进行GWAS的研究人员的合作包括来自哈佛大学(Framingham Health Study，国家肺气肿治疗试验/标准老龄化研究)、华盛顿大学(心血管健康研究)、北卡罗来纳大学(烟草和遗传学网络)和多伦多大学(安大略省患者吸烟治疗研究)的合作。这项研究的目标是：(1)使用550,000个SNPs的全基因组阵列在欧洲美国人和非裔美国人LHS受试者中进行GWAS，以个体肺功能下降速度和COPD易感性为主要结果表型；(2)利用独立人群中现有的Gwas数据交叉验证显著的相关性；(3)使用与COPD结果相关的标记测试基因-环境相互作用，特别关注烟草使用；以及(4)对反映尼古丁成瘾的标记和结果之间的关联进行测试(例如，持续戒烟者与持续吸烟者)，并验证复制人群中的显著关联。这项研究的发现将更好地了解与COPD风险相关的复杂途径及其相关表型。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a complex disease of substantial public health concern, and is the 4th leading cause of mortality globally, with morbidity and mortality expected to worsen by the year 2020. Tobacco use is a major environmental risk factor in the development of COPD; however, only 10-20% of smokers develop symptomatic disease. Animal and human studies provide support for the role of genetic factors for both smoking behavior and its associated outcomes, including lung function and other manifestations of COPD, yet only a small proportion of potentially causal genes have been identified. The Lung Health Study (LHS), a 14.5-year, multicenter, randomized clinical trial aimed to determine whether a program of smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in pulmonary function or alter COPD mortality, represents one of the largest COPD cohorts worldwide (N=5,887). As part of a previous NHLBI-funded study, we developed a DNA repository including >4,800 LHS participants. We plan to perform a genome-wide association study (GWAS) for COPD and associated quantitative traits in this well-characterized cohort and use existing GWAS datasets to validate our findings. Because we also hypothesize that some genes may contribute to nicotine addiction and thus tobacco use (the strongest environmental risk factor in COPD), we will test for association between genetic markers and this outcome, and will similarly validate those findings, and test for gene-environment interaction. A major strength of our application is the collaborative effort with colleagues at the James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research in Vancouver, and the LHS Data Coordinating Center at the University of Minnesota. Additional collaborations with investigators conducting GWAS in relevant datasets include those from Harvard University (the Framingham Health Study, the National Emphysema Treatment Trial/Normative Aging Study), University of Washington (the Cardiovascular Health Study), University of North Carolina (Tobacco and Genetics Network), and University of Toronto (Smoking Treatment for Ontario Patients Study). Goals of this study are: (1) to perform GWAS in European American and African American LHS subjects using a genome-wide array of 550,000 SNPs, with individual rate of decline of lung function and COPD susceptibility as the primary outcome phenotypes; (2) to cross-validate significant associations using existing GWAS data in independent populations; (3) to test for gene-environment interactions using markers associated with COPD outcomes, with a particular focus on tobacco use; and (4) to perform tests for association between the markers and outcomes reflecting nicotine addiction (e.g. sustained quitters vs. continuous smokers), and to validate significant associations in a replicate population. Findings from this study will provide a better understanding of the complex pathways related to risk of COPD and its associated phenotypes.