The Impact Of Nonlinear Smoking Effects In The Identification Of Gene-by-Smoking Interactions In COPD Genetics Studies

Abstract

BackgroundThe 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 CaseeControl cohort and a potential PI*Z-by-smoking interaction was identified (p¼0.03 for FEV 1 analysis, p¼0.01 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.Chronic obstructive pulmonary disease (COPD) is well suited to the study of gene-by-environment interactions since the major environmental risk factor for COPDdcigarette smokingdis known and quantifiable. With the advent of large wellpowered genome-wide association studies in COPD, the identification of such interactions may be feasible. However, there are a number of challenges to the identification of gene-by-smoking interactions in COPD: (1) the principal genetic risk factors for COPD are still in the process of being identified; (2) a variety of approaches have been used to model smoking effects; and (3) there is no empirical knowledge of the nature, extent or functional form of gene-by-smoking interactions in COPD.While cigarette smoking is easily quantifiable in terms of pack-years ((average daily number of cigarettes smoked/20 cigarettes per pack) 3 years of smoking), previous work has shown that packyears alone may be an overly simplistic means of modelling smoking exposure, and non-linear relations may be present.1 2 Many COPD genetic association analyses model smoking effects by including a pack-years term in a regression model, which assumes a linear relation between pack-years and forced expiratory volume in 1 s (FEV 1 ) or, in...

Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank

“…A non-linear decline in FEV1 in relation to increasing pack-years has been reported previously, but sex differences were not examined (30). We The biological mechanisms underlying the apparent greater susceptibility to cigarette smoke among women are unclear.…”