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

Association of IREB2 and CHRNA3polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency