Genetic Determinants of COPD in Diverse Ethnic Groups

描述(由申请人提供)：虽然吸烟是COPD发病的主要已知危险因素，但吸烟者发生气流阻塞的显著差异以及慢性气流阻塞的家族聚集性表明，遗传因素在COPD的发病机制中也是重要的。唯一被证实的COPD遗传风险因素是严重的α1-抗胰蛋白酶缺乏，只有1%-2%的COPD患者存在这种情况。已对COPD的许多候选基因变异进行了病例对照遗传关联研究，但结果并不一致。高通量SNP基因分型的最新进展使全基因组关联的研究成为可能，而不是将分析局限于候选基因或连锁区域。然而，在对数千个SNPs的遗传关联研究中涉及的多重统计测试在区分真假阳性关联方面提出了挑战。此外，单一种族群体内的遗传关联研究可能不会推广到其他群体。为了解决多重统计检验和概括性问题，我们在三个不同种族的人群中启动了病例对照COPD基因关联研究，统称为跨洲COPD遗传学研究：波兰的高加索人、韩国的亚洲人和美国的非裔美国人。我们建议将这三个研究人群分别扩大到300名COPD病例和300名吸烟控制受试者。我们将在国家肺气肿治疗试验(NETT)现有的350例高加索COPD病例和标准老龄化研究(NAS)的350例高加索吸烟对照病例中进行初步的全基因组相关性研究。随后，我们将尝试在来自波兰的COPD病例和对照的初始全基因组关联扫描中复制最有希望的关联，以确定高加索人COPD的遗传决定因素。最后，我们将在高加索人(波兰人和NETT/NAS)、韩国人和非裔美国人COPD病例和对照中的20个重复关联区域中测试密集的SNPs小组，以确定在所有四个研究人群中可能包含COPD易感基因的基因组区域。我们将利用这些研究人群之间的连锁不平衡模式的差异来定位COPD的易感基因。这项提议的总体目标是检验这样一个假设，即共同的基因决定因素影响不同种族群体中COPD的发展。

DESCRIPTION (provided by applicant): Although cigarette smoking is the major known risk factor for the development of COPD, the marked variability in the development of airflow obstruction among smokers and the familial aggregation of chronic airflow obstruction suggest that genetic factors are also important in COPD pathogenesis. The only proven genetic risk factor for COPD is severe alpha 1-antitrypsin deficiency, which is found in only 1-2% of individuals with COPD. Case-control genetic association studies have been performed with many candidate gene variants in COPD, but the results have been inconsistent. Recent progress in high-throughput SNP genotyping allows for studies of genome-wide association, rather than limiting analysis to candidate genes or regions of linkage. However, the multiple statistical tests involved in genetic association studies of thousands of SNPs raise challenges in separating true from false positive associations. In addition, genetic association studies within a single ethnic group may not generalize to other populations. In order to address both the multiple statistical testing and generalizability problems, we have initiated case-control COPD genetic association studies in three ethnically diverse populations, which are collectively known as the Transcontinental COPD Genetics Study: Caucasians in Poland, Asians in Korea, and African Americans in the U.S.. We propose to expand each of these three study populations to 300 COPD cases and 300 smoking control subjects. We will perform our initial genome-wide association study in an existing set of 350 Caucasian COPD cases from the National Emphysema Treatment Trial (NETT) and 350 Caucasian smoking controls from the Normative Aging Study (NAS). Subsequently, we will attempt to replicate the most promising associations in the initial genome-wide association scan in COPD cases and controls from Poland to identify genetic determinants of COPD in Caucasians. Finally, we will test a dense panel of SNPs in 20 replicated regions of association in Caucasian (Polish and NETT/NAS), Korean, and African-American COPD cases and controls to identify genomic regions likely to contain susceptibility genes for COPD in all four study populations. We will use the differences in linkage disequilibrium patterns between these study populations to localize susceptibility genes for COPD. The overall goal of this proposal is to test the hypothesis that shared genetic determinants influence the development of COPD in diverse ethnic groups.