Cigarette smoking is the major environmental risk factor for the development of chronic obstructivepulmonary disease (COPD), but genetic determinants other than alphal-antitrypsin deficiency likely alsoinfluence COPD susceptibility. Genetic association studies using multiple study designs, multiple populationsamples, and appropriate adjustments for population stratification are essential to identify and replicate keygenetic association results. In Project 2, we have selected 100 candidate genes for COPD from severalsources, including previously reported genetic associationsto COPD; multiply replicated geneticassociations to asthma, and genes identified by animal models of COPD. A panel of 1536 SNPs (LD-tagging SNPs, previously associated SNPs, and non-synonymous SNPs) in these candidate genes will betested in 400 COPD cases from the National Emphysema Treatment Trial (NETT) and 400 control subjectsfrom the Normative Aging Study (NAS). Based on these COPD case-control analyses, a subset of 20 geneswill be selected for more intensive study. SNPs in these 20 genes will be tested for association in familiesfrom the Boston Early-Onset COPD Study to COPD (GOLD Stage > 2) and to three quantitative COPD-related phenotypes (FEV1f FEV^FVC, and bronchodilator responsiveness). Based on combined p valuesfrom the case-control and family-based analyses, significantly associated COPD genes will be identified. Alarger number of SNPs per gene (to provide LD-tagging of HapMap SNPs in Caucasian and Africanpopulations with r2 > 0.95) in the significantly associated COPD genes will be studied in the NETT COPDcase and NAS control populations, Boston Early-Onset COPD families, and African-American COPD casesand controls. Positional candidate genes from animal model QTL studies (Project 3) and genes located nearsignificant SNPs in the asthma genome-wide association study (Project 1) will also be included in this finalpanel of 1536 SNPs. Genes with SNPs that show significant association with COPD only, asthma only, andboth asthma and COPD will be identified. The set of COPD susceptibility genes resulting from theseassociation studies will undergo additional exploratory genetic association analysis including phenotypes foremphysema distribution and severity (in COPD NETT cases).
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