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Abstract
Background The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV1); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.
Methods The relationship between FEV1 and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects.
Results Non-linear relationships between smoking and FEV1 were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV1 is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case–Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV1 analysis, p=0.01 for COPD susceptibility analysis).
Conclusion In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV1 is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.
- Smoking
- FEV1
- gene-by-environment interaction
- COPD
- gene
- COPD epidemiology
- tobacco and the lung
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Supplementary materials
Web Only Data thx.2010.146118
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Footnotes
See Editorial, p 841
Linked articles 154195.
The ICGN (International COPD Genetics Network) investigators are: Alvar Agusti (Hospital Universitari Son Dureta, Mallorca, Spain); Peter Calverley (University of Liverpool, Liverpool, UK); Claudio F Donner (S. Maugeri Foundation, Veruno, Novara, Italy); Robert D Levy (James Hogg iCAPTURE Centre, University of British Columbia, Vancouver, Canada); David Lomas (University of Cambridge, Cambridge, UK); Barry J Make (National Jewish Health, Denver, Colorado, USA); Wayne Anderson (GlaxoSmithKline, Research Triangle Park, North Carolina, USA); Peter Pare (James Hogg iCAPTURE Centre, University of British Columbia, Vancouver, Canada); Sreekumar Pillai (GlaxoSmithKline, Research Triangle Park, North Carolina, USA); Stephen Rennard (University of Nebraska, Omaha, Nebraska, USA); Emiel Wouters (University Hospital Maastricht, Maastricht, The Netherlands); Edwin K Silverman (The Channing Laboratory and Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA); and Jørgen Vestbo (Hvidovre Hospital, Copenhagen, Denmark). The AATGM (Alpha-1 Antitrypsin Genetic Modifiers Study) investigators are: Alan Barker (University of Oregon), Mark Brantly (University of Florida), Edward J Campbell (Utah Valley Pulmonary Clinic), Edward Eden (St Luke's/Roosevelt Hospital) N Gerard McElvaney (Beaumont Hospital, Dublin), Stephen Rennard (University of Nebraska), Robert Sandhaus (National Jewish Health), Edwin K Silverman (Brigham and Women's Hospital), James Stocks (University of Texas Health Center at Tyler), James Stoller (Cleveland Clinic), Charlie Strange (Medical University of South Carolina), Gerard Turino (St Luke's/Roosevelt Hospital).
Funding The authors were supported by the following grants: K08HL102265, UL1 RR025752, R01 HL084323, R01 HL075478, U01 089856, and P01 HL083069. The International COPD Genetics Network is funded by a grant from GlaxoSmithKline.
Competing interests PDP served on the Advisory Board for Talecris Biotherapeutics and received grant support from GSK, Merck (≥$100 001), the NIH ($50,001–100,000), CIHR (Canada) and AllerGenNCE (≥$100 001). EKS received grant support and consulting fees from GlaxoSmithKline for studies of COPD genetics and honoraria and consulting fees from AstraZeneca. SR has consulted or participated in advisory boards for Able Associates, Adelphia Research, Almirall/Prescott, APT Pharma/Britnall, Aradigm, AstraZeneca, Boehringer Ingelheim, Chiesi, CommonHealth, Consult Complete, COPDForum, DataMonitor, Decision Resources, Defined Health, Dey, Dunn Group, Eaton Associates, Equinox, Gerson, GlaxoSmithKline, Infomed, KOL Connection, M Pankove, MedaCorp, MDRx Financial, Mpex, Novartis, Nycomed, Oriel Therapeutics, Otsuka, Pennside Partners, Pfizer (Varenicline), PharmaVentures, Pharmaxis, Price Waterhouse, Propagate, Pulmatrix, Reckner Associates, Recruiting Resources, Roche, Schlesinger Medical, Scimed, Sudler and Hennessey, TargeGen, Theravance, UBC, Uptake Medical and VantagePoint Management; has given lectures for the American Thoracic Society, AstraZeneca, Boehringer Ingelheim, California Allergy Society, Creative Educational Concept, France Foundation, Information TV, Network for Continuing Ed, Novartis, Pfizer and SOMA; and has received industry-sponsored grants from AstraZeneca, Biomarck, Centocor, Mpex, Nabi, Novartis and Otsuka. DAL has received grant support, consultancy fees and honoraria from GlaxoSmithKline, consultancy fees from Talecris Biotherapeutics, Genzyme and Amicus Therapeutics and honoraria from LKB. JV has received honoraria for consulting and presenting for pharmaceutical companies with an interest in COPD, and is an investigator on the ECLIPSE study and the International COPD Genetics Network, both sponsored by GlaxoSmithKline.
Ethics approval This study was conducted with the approval of the Partners IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
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