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.
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Funding This work was supported by US National Institutes of Health (NIH) grants R01 HL075478, R01 HL084323, P01 HL0830B9, U01 HL08985B (Silverman), K12HL089990 (Cho), and U01 HL089897 (Crapo) . The National Emphysema Treatment Trial was supported by the National Heart, Lung, and Blood Institute contracts ( N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR761 O6, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119 ), the Centers for Medicare and Medicaid Services, and the Agency for Healthcare Research and Quality. The Norway cohort and the ECLIPSE study ( http://www.Clinicaltrials.gov identifier NCT00292552 ; GSK Code SCO104960) are funded by GlaxoSmithKline. The COPDGene project was supported by Award Number U01HL089897 and Award Number U01HL089856 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Pfizer, Boehrlnger Ingelhelm, Novartis and Sepracor. M. Siedlinski is a recipient of a post-doctoral fellowship from the Niels Stensen Foundation.
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