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

Nicotine Tob Res. 2016 Sep;18(9):1903-9. doi: 10.1093/ntr/ntw129. Epub 2016 May 6.


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.

Implications: Studies relying only on self report of smoking status to assess or adjust for the impact of smoking may not fully capture its effect and will lead to residual confounding of results.

Trial registration: NCT00292552.

MeSH terms

  • Adult
  • Aged
  • Carbon Monoxide / analysis
  • Carrier Proteins / genetics
  • Female
  • Gene Expression
  • Humans
  • Male
  • Membrane Glycoproteins
  • Membrane Proteins / genetics
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Phenotype
  • Pulmonary Disease, Chronic Obstructive / etiology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Peptide / genetics
  • Risk Factors
  • Self Report*
  • Smoking / adverse effects
  • Smoking / blood
  • Smoking / genetics*
  • Transcriptome
  • alpha-L-Fucosidase / genetics


  • Carrier Proteins
  • FUCA1 protein, human
  • GPR15 protein, human
  • LRRN3 protein, human
  • Membrane Glycoproteins
  • Membrane Proteins
  • Neoplasm Proteins
  • PID1 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Carbon Monoxide
  • alpha-L-Fucosidase

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