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

Respiratory Research

Dawn L DeMeo^1,12  Robert A Stockley⁶  Edwin K Silverman^1,12  Gerard Turino¹  Charlie Strange⁹  James K Stoller⁷  James M Stocks^1,13  Robert A Sandhaus³  Stephen I Rennard^1,11  Gerard McElvaney⁸  Edward Eden¹  Edward J Campbell^1,14  Mark L Brantly²  Alan F Barker⁴  Alice M Wood⁵  Woo Jin Kim^1,10 

[1] St. Luke's/Roosevelt Hospital, New York, NY, USA;University of Florida, Gainesville, FL, USA;National Jewish Health, Denver, CO, USA;Oregon Health and Science University, Portland, OR, USA;School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK;Lung Investigation Unit, University Hospitals Birmingham, Birmingham, UK;Cleveland Clinic, Cleveland, OH, USA;Beaumont Hospital, Dublin, Ireland;Medical University of South Carolina, Charleston, SC, USA;Department of Internal Medicine, Kangwon National University, Chuncheon, South Korea;University of Nebraska, Omaha, NE, USA;Channing Laboratory and the Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA;University of Texas at Tyler, Tyler, TX, USA;Intermountain Health Care, Provo, and Heredilab, Inc, Salt Lake City, UT, USA

关键词: IREB2;    Genetic modifiers;    Genetic association analysis;    Chronic obstructive pulmonary disease;    CHRNA3;   

Others  :  796746
DOI  :  10.1186/1465-9921-13-16

 received in 2011-12-11, accepted in 2012-02-22,  发布年份 2012

【 摘 要 】

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. 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.

Results

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.

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.

【 授权许可】

   
2012 Kim et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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