Genetic Determinants of COPD in Diverse Ethnic Groups

描述（由申请方提供）：尽管吸烟是COPD发展的主要已知风险因素，但吸烟者气流阻塞发展的显著差异和慢性气流阻塞的家族聚集性表明遗传因素在COPD发病机制中也很重要。COPD的唯一已证实的遗传风险因素是严重的α 1-抗胰蛋白酶缺乏症，仅在1-2%的COPD患者中发现。已对COPD中的许多候选基因变异进行了病例对照遗传关联研究，但结果不一致。高通量SNP基因分型的最新进展允许全基因组关联的研究，而不是将分析局限于候选基因或连锁区域。然而，在数千个SNP的遗传关联研究中涉及的多重统计检验在区分真与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无法推广到其他人群。为了解决多重统计检验和普遍性问题，我们在三个不同种族的人群中开展了病例对照COPD遗传关联研究，这些人群统称为横贯大陆COPD遗传学研究：波兰的高加索人、韩国的亚洲人和美国的非洲裔美国人。我们建议将这三个研究人群分别扩大到300例COPD病例和300例吸烟对照受试者。我们将在来自国家肺气肿治疗试验（NETT）的350例白人COPD病例和来自规范性衰老研究（NAS）的350例白人吸烟对照中进行初步的全基因组关联研究。随后，我们将尝试在来自波兰的COPD病例和对照中复制最初全基因组关联扫描中最有希望的关联，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）、韩国人和非洲裔美国人COPD病例和对照中检测20个重复关联区域中的一组密集SNP，以确定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连锁不平衡模式的差异来定位COPD的易感基因。该提案的总体目标是检验共享遗传决定因素影响不同种族群体中COPD发展的假设。

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.