title: 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.
authors.affiliation: Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Siedlinski
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Wayne
authors.initials: W
authors.lastname: Anderson
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Kong
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: John E
authors.initials: JE
authors.lastname: Hokanson
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D000367:Age Factors; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D004247:DNA / Q000235:genetics*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D012907:Smoking / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D016540:Smoking Cessation; D014481:United States / Q000453:epidemiology
chemical_list: D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D004299:Dopamine beta-Hydroxylase