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

• Main Authors: Kim Woo Jin, Wood Alice M, Barker Alan F, Brantly Mark L, Campbell Edward J, Eden Edward, McElvaney Gerard, Rennard Stephen I, Sandhaus Robert A, Stocks James M, Stoller James K, Strange Charlie, Turino Gerard, Silverman Edwin K, Stockley Robert A, DeMeo Dawn L
• Format: Article
• Language: English
• Published: BMC 2012-02-01
• Series: Respiratory Research
• Subjects: <it>CHRNA3</it>; Chronic obstructive pulmonary disease; Genetic association analysis; Genetic modifiers; <it>IREB2</it>
• Online Access: http://respiratory-research.com/content/13/1/16
• ISSN: 1465-9921

<p>Abstract</p> <p>Background</p> <p>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 <it>CHRNA3 </it>(cholinergic nicotine receptor alpha3) and <it>IREB2 </it>(iron regulatory binding protein 2).</p> <p>We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.</p> <p>Methods</p> <p>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 <it>LOC123688, CHRNA3 </it>and <it>IREB2 </it>were selected for genotyping. FEV₁percent 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.</p> <p>Results</p> <p>Three SNPs (rs2568494 in <it>IREB2</it>, rs8034191 in <it>LOC123688</it>, and rs1051730 in <it>CHRNA3</it>) were associated with pre-bronchodilator FEV₁percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV₁percent 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.</p> <p>Conclusions</p> <p><it>IREB2 </it>and <it>CHRNA3 </it>are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.</p>