Background: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be\r\ninfluenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD\r\nhave demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3\r\n(cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).\r\nWe investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in\r\nAAT deficiency.\r\nMethods: The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication\r\ncohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2\r\nwere selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative\r\nphenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication\r\nset, general linear models were used for quantitative phenotypes and logistic regression models were used for the\r\npresence/absence of emphysema or COPD.\r\nResults: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with\r\npre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and\r\nrs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC\r\nratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly\r\nassociated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.\r\nConclusions: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe\r\nAAT deficiency and may be sex-specific in their impact.
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