title: Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency.
abstract: 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.
authors.affiliation: Channing Laboratory and the Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Kim
authors.forename: Alice M
authors.initials: AM
authors.lastname: Wood
authors.forename: Alan F
authors.initials: AF
authors.lastname: Barker
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Campbell
authors.forename: Edward
authors.initials: E
authors.lastname: Eden
authors.forename: Gerard
authors.initials: G
authors.lastname: McElvaney
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sandhaus
authors.forename: James M
authors.initials: JM
authors.lastname: Stocks
authors.forename: James K
authors.initials: JK
authors.lastname: Stoller
authors.forename: Charlie
authors.initials: C
authors.lastname: Strange
authors.forename: Gerard
authors.initials: G
authors.lastname: Turino
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stockley
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
mesh_terms: D000328:Adult; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D005260:Female; D006801:Humans; D035942:Iron Regulatory Protein 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D011656:Pulmonary Emphysema / Q000235:genetics / Q000503:physiopathology; D011978:Receptors, Nicotinic / Q000235:genetics*; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D012737:Sex Factors; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics* / Q000503:physiopathology
chemical_list: D035942:Iron Regulatory Protein 2; D011978:Receptors, Nicotinic