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.

Links

PMC Free PDF

PMC Free Full Text

Publisher Full Text

Authors

Kim WJ, Wood AM, Barker AF, Brantly ML, Campbell EJ, Eden E, McElvaney G, Rennard SI, Sandhaus RA, Stocks JM, Stoller JK, Strange C, Turino G, Silverman EK, Stockley RA, Demeo DL

Institution

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

Source

Respiratory research 13: 2012 pg 16

MeSH

Adult
Chromosomes, Human, Pair 15
Female
Humans
Iron Regulatory Protein 2
Male
Middle Aged
Polymorphism, Single Nucleotide
Pulmonary Disease, Chronic Obstructive
Pulmonary Emphysema
Receptors, Nicotinic
Respiratory Function Tests
Severity of Illness Index
Sex Factors
alpha 1-Antitrypsin Deficiency

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22356581