Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies.

TitleImpact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies.
Publication TypeJournal Article
Year of Publication2011
AuthorsCastaldi, PJ, DeMeo, DL, Hersh, CP, Lomas, DA, Soerheim, IC, Gulsvik, A, Bakke, P, Rennard, S, Pare, P, Vestbo, J, Silverman, EK
Corporate AuthorsAATGM Investigators, ICGN Investigators
JournalThorax
Volume66
Issue10
Pagination903-9
Date Published2011 Oct
ISSN1468-3296
Keywordsalpha 1-Antitrypsin, DNA, Female, Follow-Up Studies, Forced Expiratory Volume, Genome-Wide Association Study, Genotype, Humans, Incidence, Male, Middle Aged, Norway, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests, Retrospective Studies, Risk Factors, Smoking
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 (FEV(1)); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.

METHODS: The relationship between FEV(1) 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 FEV(1) were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV(1) 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 FEV(1) 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 FEV(1) 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.

DOI10.1136/thx.2010.146118
Alternate JournalThorax
PubMed ID21163806
PubMed Central IDPMC3312798
Grant ListG0901786 / / Medical Research Council / United Kingdom
K08 HL102265 / HL / NHLBI NIH HHS / United States
K08 HL102265-01 / HL / NHLBI NIH HHS / United States
K08 HL102265-02 / HL / NHLBI NIH HHS / United States
K08HL102265 / HL / NHLBI NIH HHS / United States
P01 HL083069 / HL / NHLBI NIH HHS / United States
P01 HL083069 / HL / NHLBI NIH HHS / United States
P01 HL083069-01A1 / HL / NHLBI NIH HHS / United States
R01 HL075478 / HL / NHLBI NIH HHS / United States
R01 HL084323 / HL / NHLBI NIH HHS / United States
R01 HL084323 / HL / NHLBI NIH HHS / United States
R01 HL084323-01A2 / HL / NHLBI NIH HHS / United States
U01 089856 / / PHS HHS / United States
U01 HL089856 / HL / NHLBI NIH HHS / United States
U01 HL089856-01A1 / HL / NHLBI NIH HHS / United States
UL1 RR025752 / RR / NCRR NIH HHS / United States
UL1 RR025752-01 / RR / NCRR NIH HHS / United States