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.
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