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

ABSTRACT: 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.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.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).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.

SUBMITTER: Castaldi PJ

PROVIDER: S-EPMC3312798 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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

Castaldi P J PJ Demeo D L DL Hersh C P CP Lomas D A DA Soerheim I C IC Gulsvik A A Bakke P P Rennard S S Pare P P Vestbo J J Silverman E K EK

Thorax 20101216 10

<h4>Background</h4>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.<h4>Methods</h4>The relationship between FEV(1) and pack-years of ...[more]

PMID: 21163806

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Project description:Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic inflammation and irreversible airway obstruction. Cigarette smoking is the predominant risk factor for developing COPD. It is well-known that the COPD is also strongly associated with an increased risk of developing lung cancer. Cigarette smoke contains elevated concentrations of oxidants and various carcinogens (e.g., tobacco-derived nitrosamines) that can cause oxidative and alkylating stresses, which can also arise from inflammation. However, it is surprising that, except for oxidative stress, little information is available on the burden of alkylating stress and the detoxification efficiency of tobacco-derived carcinogens in COPD patients. In this study, we used LC-MS/MS to measure the archetypical tobacco-specific carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), three biomarkers of oxidative stress (8-oxo-7,8-dihydroguanine, 8-oxoGua; 8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxodGuo; 8-oxo-7,8-dihydroguanosine, 8-oxoGuo) and two biomarkers of alkylating stress (N7-methylguanine, N7-MeGua and N3-methyladenine, N3-MeAde), in the urine of smoking and non-smoking COPD patients and healthy controls. Our results showed that not only was oxidative stress significantly elevated in the COPD patients compared to the controls, but also alkylating stress. Significantly, levels of alkylating stress (i.e., N7-MeGua) were highly correlated with the COPD severity and not affected by age and smoking status. Furthermore, COPD smokers had significantly higher ratios of free NNAL to the total NNAL than control smokers, implying a lower detoxification efficiency of NNK in COPD smokers. This ratio was even higher in COPD smokers with stages 3-4 than in COPD smokers with stages 1-2. Taken together, our results demonstrated that the detoxification efficiency of tobacco-derived carcinogens (e.g., NNK) was associated with the pathogenesis and possibly the progression of COPD. In addition to oxidative stress, alkylating stress derived from chronic inflammation appears to be also dominant in COPD patients.

Dataset Information

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

Publications

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

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