Abstract
BackgroundThe 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.MethodsThe 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. FEV1 percent of predicted and FEV1/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.ResultsThree SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/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.ConclusionsIREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.
Highlights
The development of Chronic obstructive pulmonary disease (COPD) in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes
Iron regulatory binding protein 2 (IREB2) was identified as a potential COPD susceptibility gene using an integrative genomics approach with gene expression analysis of lung tissue samples followed by genetic association analysis [18]
Demographic characteristics The mean age of subjects was 52.2 years, and mean postbronchodilator FEV1 was 65.9% predicted in the AAT Genetic Modifiers Study and 50.3 years and 53.8% predicted in the UK AATD National Registry, respectively (Table 1)
Summary
Study subjects The current analysis included 378 subjects with severe AAT deficiency (protease inhibitor [PI] ZZ) from 167 families in the AAT Genetic Modifiers Study. The presence of emphysema was determined by the appearance of the scan and density mask analysis of slices at the level of the aortic arch (representing the upper zone) and the inferior pulmonary vein (representing the lower zone) using a threshold of -910 Hounsfield Units (HU) This HU threshold has been validated against physiological measures in AATD [22]. In UK AATD National Registry study, genotyping was carried out using TaqMan® technologies (Applied Biosystems, UK) on an ABI7900 HT for 3 SNPs associated in the test dataset (rs2568494, IREB2; rs8034191, LOC123688; rs1051730, CHRNA3). Family-based association analysis was performed using PBAT software version 3.6 [26] assuming additive genetic models, adjusting for pack-years and pack-years of cigarette smoking, under the null hypothesis of no linkage and no association in the AAT Genetic Modifiers Study. Gender stratification and SNP-by-gender and SNP-by-smoking interaction analyses were carried out, as in the test dataset
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