Open Access Highly Accessed Open Badges Research

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

Woo Jin Kim1, Alice M Wood2, Alan F Barker3, Mark L Brantly4, Edward J Campbell5, Edward Eden6, Gerard McElvaney7, Stephen I Rennard8, Robert A Sandhaus9, James M Stocks10, James K Stoller11, Charlie Strange12, Gerard Turino13, Edwin K Silverman14, Robert A Stockley15 and Dawn L DeMeo14*

Author Affiliations

1 Department of Internal Medicine, Kangwon National University, Chuncheon, South Korea

2 School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK

3 Oregon Health and Science University, Portland, OR, USA

4 University of Florida, Gainesville, FL, USA

5 Intermountain Health Care, Provo, and Heredilab, Inc, Salt Lake City, UT, USA

6 St. Luke's/Roosevelt Hospital, New York, NY, USA

7 Beaumont Hospital, Dublin, Ireland

8 University of Nebraska, Omaha, NE, USA

9 National Jewish Health, Denver, CO, USA

10 University of Texas at Tyler, Tyler, TX, USA

11 Cleveland Clinic, Cleveland, OH, USA

12 Medical University of South Carolina, Charleston, SC, USA

13 St. Luke's/Roosevelt Hospital, New York, NY, USA

14 Channing Laboratory and the Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA

15 Lung Investigation Unit, University Hospitals Birmingham, Birmingham, UK

For all author emails, please log on.

Respiratory Research 2012, 13:16  doi:10.1186/1465-9921-13-16

Published: 22 February 2012



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.


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. 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.


Three 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.


IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.

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