Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency

Woo Jin Kim, Alice M. Wood, Alan Barker, Mark L. Brantly, Edward J. Campbell, Edward Eden, Gerard McElvaney, Stephen I. Rennard, Robert A. Sandhaus, James M. Stocks, James K. Stoller, Charlie Strange, Gerard Turino, Edwin K. Silverman, Robert A. Stockley, Dawn L. DeMeo

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31 Scopus citations


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.

Original languageEnglish (US)
Article number16
JournalRespiratory Research
Publication statusPublished - Feb 22 2012



  • CHRNA3
  • Chronic obstructive pulmonary disease
  • Genetic association analysis
  • Genetic modifiers
  • IREB2

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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