PT  - JOURNAL ARTICLE
AU  - Castaldi, P J
AU  - Demeo, D L
AU  - Hersh, C P
AU  - Lomas, D A
AU  - Soerheim, I C
AU  - Gulsvik, A
AU  - Bakke, P
AU  - Rennard, S
AU  - Pare, P
AU  - Vestbo, J
AU  - AATGM Investigators
AU  - ICGN Investigators
AU  - Silverman, E K
TI  - Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies
AID  - 10.1136/thx.2010.146118
DP  - 2011 Oct 01
TA  - Thorax
PG  - 903--909
VI  - 66
IP  - 10
4099  - http://thorax.bmj.com/content/66/10/903.short
4100  - http://thorax.bmj.com/content/66/10/903.full
SO  - Thorax2011 Oct 01; 66
AB  - 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.