The Effect of Different Case Definitions of Current Smoking on the Discovery of Smoking-Related Blood Gene Expression Signatures in Chronic Obstructive Pulmonary Disease

Abstract

Introduction: Smoking is the number one modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD). Clinical, epidemiological and increasingly "omics" studies assess or adjust for current smoking status using only self-report, which may be inaccurate. Objective measures such as exhaled carbon monoxide (eCO) may also be problematic owing to limitations in the measurements and the relatively short half life of the molecule. In this study, we determined the impact of different case definitions of current cigarette smoking on gene expression in peripheral blood of patients with COPD. Methods: Peripheral blood gene expression from 573 former-and current-smokers with COPD in the ECLIPSE study was used to find genes whose expression was associated with smoking status. Current smoking was defined using self-report, eCO concentrations, or both. Linear regression was used to determine the association of current smoking status with gene expression adjusting for age, sex and propensity score. Pathway enrichment analyses were performed on genes with P < .001. Result: Using self-report or eCO, only two genes were differentially expressed between current and ex-smokers, with no enrichment in biological processes. When current smoking was defined using both eCO and self-report, four genes were differentially expressed (LRRN3, PID1, FUCA1, GPR15) with enrichment in 40 biological pathways related to metabolic processes, response to hypoxia and hormonal stimulus. Additionally, the combined definition provided better distributions of test statistics for differential gene expression. Conclusion: A combined phenotype of eCO and self report allows for better discovery of genes and pathways related to current smoking.

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

“…Similarly, when we included both former and never smokers in our replication cohort vs. current smokers, and despite the increase in sample size, fewer genes were actually replicated compared to when we only included never vs. current smokers (Figure 3A-3C). This is consistent with previous findings from our group highlighting the importance of case definition of smokers on gene signature discovery 41 .…”

“…First, the sample size, although large, may not be sufficient to detect and replicate genes with smaller effects. Second, we used self-reported smoking status based on available data on GEO but self-reports may not accurately reflect smoking habits 41 . Third, we studied changes in airway epithelium given its role in the pathogenesis of lung diseases, but smoking may also affect other cell types such as immune and infiltrating cells in the airways.…”

Smoking aggravates ventricular arrhythmic events in non-ischemic dilated cardiomyopathy associated with a late gadolinium enhancement in cardiac MRI

“…Smoking has been reported to affect endothelial cell dysfunction such as endothelial cell injury, increased endothelial permeability, nitric oxide production, and the binding of inflammatory cells forming atherosclerotic plaques 36 , 37 . There was also a report that gene expressions related to metabolism, hypoxia, and a response to hormone stimulation were differentially expressed in smokers as compared to non-smokers 38 . Furthermore, one of the mechanism by which smoking affects cardiovascular disease is through chronic sympathetic activation as demonstrated by the increase in plasma epinephrine concentration levels, heart rate, systolic, diastolic, blood pressure and CO levels.…”

The genetics of smoking in individuals with chronic obstructive pulmonary disease

“…However, most of these studies have relied on self-reported smoking status as either the phenotype of interest or one of the covariates to “adjust” tobacco exposure. Self-report is vulnerable to reporting and recall bias and has been shown to consistently underestimate total tobacco exposure [ 10 , 11 ], which may result in residual confounding [ 12 ]. One way to mitigate this risk is to use an objective biochemical assay to validate self-reports of tobacco use.…”