Genome-wide association study of smoking behaviours in patients with COPD

Abstract

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10(-6). Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10(-5) for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.

Trial registration: ClinicalTrials.gov NCT00292552.

Figure 1. Regional association plots of two loci including SNPs associated with age at smoking initiation with meta-analytic p<10⁻⁶

Dots correspond to meta-analyzed SNPs. Color of dots corresponds to r² (linkage disequilibrium (LD) coefficient in the HapMap II CEU population; grey dots correspond to SNPs with missing LD information) relative to the most significantly associated SNP (depicted with diamond) in the region i.e. rs13408379 (top figure) and rs9380362 (bottom figure).

Figure 2. Regional association plots of the candidate loci centered on CHRNA3 (top) and CYP2A6 (bottom) and their associations with lifetime average number of cigarettes smoked per day

Dots correspond to meta-analyzed SNPs. Color of dots correspond to r² (linkage disequilibrium (LD) coefficient in the HapMap II CEU population; grey dots correspond to SNPs with missing LD information) relative to the most significantly associated SNP in the region (depicted with diamond) i.e. rs1051730 in the CHRNA3 (top figure) and rs1496402 (bottom figure; the second top SNP in this region is a nonsynonymous (Leu160His) rs1801272 SNP in the CYP2A6). CHRNA3=alpha-nicotinic acetylcholine receptor 3; CYP2A6=Cytochrome P450 2A6