Genome-wide association study of smoking behaviours in patients with COPD
- Mateusz Siedlinski1,
- Michael H Cho1,2,
- Per Bakke3,
- Amund Gulsvik3,
- David A Lomas4,
- Wayne Anderson5,
- Xiangyang Kong6,
- Stephen I Rennard7,
- Terri H Beaty8,
- John E Hokanson9,
- James D Crapo10,
- Edwin K Silverman1,2,
- the COPDGene Investigators and ECLIPSE Investigators
- 1Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- 3Department of Thoracic Medicine, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway
- 4Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
- 5GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, USA
- 6GlaxoSmithKline Research and Development, King of Prussia, Pennsylvania, USA
- 7Department of Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- 8Johns Hopkins School of Public Health, Baltimore, Maryland, USA
- 9Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
- 10Department of Medicine, National Jewish Health, Denver, Colorado, USA
- Correspondence to Edwin K Silverman, 181 Longwood Avenue, Boston, MA 02115, USA;
Contributors funding WA, JDC, EKS; concept and design: MS, EKS; data collection: PB, AG, DAL, WA, SIR, JDC, EKS; data analysis: MS, MHC, EKS; statistical support: MS, MHC, XK, THB, JEH, EKS; manuscript writing/editing: all authors.
- Received 8 March 2011
- Accepted 16 May 2011
- Published Online First 16 June 2011
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.
- chronic obstructive pulmonary disease (COPD)
- genome-wide association study (GWAS)
- smoking behaviours
- single nucleotide polymorphism (SNP)
- COPD epidemiology
- oxidative stress
- tobacco and the lung
- COPD pharmacology
- COPD mechanisms
- α1 antitrypsin deficiency
- COPD exacerbations
This article is based on research that is funded in part by grants from the National Institute of Health (NIH) and is therefore subject to the mandatory NIH Public Access Policy. The final, peer-reviewed manuscript must be deposited with the PubMed Central (PMC) database upon acceptance for publication and be made publicly accessible no later than 12 months after publication.
Funding This work was supported by US National Institutes of Health (NIH) grants R01 HL075478, R01 HL084323, P01 HL083069, U01 HL089856 (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, N01HR76106, 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, Boehringer Ingelheim, Novartis and Sepracor. M. Siedlinski is a recipient of a post-doctoral fellowship from the Niels Stensen Foundation.
Competing interests No competing interests: MS, AG, GlaxoSmithKline employee: WA, XK, NIH grant: JEH, THB, EKS, JDC, GlaxoSmithKline grant: EKS, DAL, PB, COPD Foundation grant: EKS, JDC, GlaxoSmithKline consulting fee or honorarium and support for travel to meetings for the study or other purposes: EKS, DAL, COPD Foundation support for travel to meetings for the study or other purposes: EKS, JDC, AstraZeneca and GlaxoSmithKline—payment for lectures including service on speakers bureaus and consultancy (outside the submitted work): EKS, PB, Pfizer—payment for lectures including service on speakers bureaus and consultancy (outside the submitted work): PB, GlaxoSmithKline—board membership, consultancy, payment for lectures including service on speakers bureaus and consultancy (outside the submitted work): DAL, Boehringer Ingelheim consultancy (outside the submitted work): DAL, GlaxoSmithKline fees for participation in review activities such as data monitoring boards, statistical analysis, end point committees, and the like: DAL, Consulting fee or honorarium from AstraZeneca, Novartis, Otsuka: SIR, Grant from AstraZeneca, Biomarck, Centocor, Mpex, Nabi, Novartis, Otsuka: SIR, Almirall, Novartis, Nycomed, Pfizer board membership (outside the submitted work): SIR, Almirall, AstraZeneca, Boehringer Ingelheim, California Allergy Society, Creative Educational Concept, France Foundation, GlaxoSmithKline, Information TV, Network for Continuing Education, Novartis, Nycomed, Pfizer—travel/accommodations expenses covered or reimbursed (outside the submitted work): SIR, Able Associates, Adelphi Research, APT Pharma/Britnall, Aradigm, AstraZeneca, Boehringer Ingelheim, Chiesi, Common Health, Consult Complete, COPDForum, Data Monitor, Decision Resource, Defined Health, Dey, Dunn Group, Easton Associates, Equinox, Gerson, GlaxoSmithKline, Infomed, KOL Connection, M. Pankove, MedaCorp, MDRx Financial, Mpex, Oriel Therapeutics, Otsuka, Pennside, PharmaVentures, Pharmaxis, Price Waterhouse, Propagate, Pulmatrix, Reckner Associates, Recruiting Resources, Roche, Schlesinger Medical, Scimed, Sudler and Hennessey, TargeGen, Theravance, UBC, Uptake Medical, VantagePoint Mangement—consultancy (outside the submitted work): SIR.
Ethics approval Partners Human Research Committee and IRBs at each clinical center.
Provenance and peer review Not commissioned; externally peer reviewed.