Chest
Volume 133, Issue 6, June 2008, Pages 1344-1353
Journal home page for Chest

Original Research
COPD
Variability in Small Airway Epithelial Gene Expression Among Normal Smokers

https://doi.org/10.1378/chest.07-2245Get rights and content

Background

Despite overwhelming data that cigarette smoking causes COPD, only a minority of long-term smokers are affected, strongly suggesting that genetic factors modify susceptibility to this disease. We hypothesized that individual variations exist in the response to cigarette smoking, with variability among smokers in expression levels of protective/susceptibility genes.

Methods

Affymetrix arrays and quantitative polymerase chain reaction were used to assess the variability of gene expression in the small airway epithelium obtained by fiberoptic bronchoscopy of 18 normal nonsmokers, 18 normal smokers, and 18 smokers with COPD.

Results

We identified 201 probe sets representing 152 smoking-responsive genes that were significantly up-regulated or down-regulated, and assessed the coefficient of variation in expression levels among the study population. Variation was a reproducible property of each gene as assessed by different microarray probe sets and real-time polymerase chain reaction, and was observed in both normal smokers and smokers with COPD. Greater individual variability was found in smokers with COPD than in normal smokers. The majority of these highly variable smoking-responsive genes were in the functional categories of signal transduction, xenobiotic degradation, metabolism, transport, oxidant related, and transcription. A similar pattern of the same highly variable genes was observed in an independent data set.

Conclusions

We propose that genetic diversity is likely within this subset of genes, with highly variable individual-to-individual responses of the small airway epithelium to smoking, and that this subset of genes represents putative candidates for assessment of susceptibility/protection from disease in future gene-based epidemiologic studies of smokers' risk for COPD.

Section snippets

Study Population

After signing informed consent, subjects were evaluated in the Weill Medical College of Cornell University National Institutes of Health General Clinical Research Center under an Institutional Review Board-approved clinical protocol. They were assessed by standard history, physical examination, CBC count, coagulation studies, liver function tests, urine studies, chest radiography, ECG, and pulmonary function testing. Fifty-four subjects in this study included three groups (Table 1): normal

Small Airway Epithelium

The cell number, purity, and differential cell counts for the samples recovered from the small airway epithelium of the normal nonsmokers, normal smokers, and smokers with COPD were similar (Table 1). A range of 2.5 to 10.1 × 106 cells were recovered from all groups (p>0.08, comparing all samples by ANOVA). There were fewer inflammatory cells (p < 0.03) and secretory cells (p < 0.01) and more basal cells (p < 0.02) in nonsmokers than in the other two groups, although the proportion of ciliated

Discussion

In this study, we have assessed individual-to-individual variability in cigarette smoking-induced changes in messenger RNA expression levels in the small airway epithelium, the cell population that takes the brunt of the stress of smoking and the initial site of pathologic changes of COPD.1, 21, 22, 23, 24, 28 The data demonstrate that among the 201 probe sets representing 152 genes in the small airway epithelium that smoking induces to be significantly up-regulated or down-regulated in normal

Acknowledgment

We thank J. Xiang in the Micoarray Core Facility for help with the chip evaluation, A. Heguy for help with data analysis, and T. Virgin-Bryan and N. Mohamed for help with preparing the article.

References (51)

  • CP Hersh et al.

    Genetic association analysis of functional impairment in chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2006)
  • K Juul et al.

    Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2006)
  • MC Matheson et al.

    β2-adrenergic receptor polymorphisms are associated with asthma and COPD in adults

    J Hum Genet

    (2006)
  • S Chappell et al.

    Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease

    Hum Mutat

    (2006)
  • WO Cookson

    State of the art: genetics and genomics of chronic obstructive pulmonary disease

    Proc Am Thorac Soc

    (2006)
  • NA Molfino

    Current thinking on genetics of chronic obstructive pulmonary disease

    Curr Opin Pulm Med

    (2007)
  • EK Silverman

    Progress in chronic obstructive pulmonary disease genetics

    Proc Am Thorac Soc

    (2006)
  • AM Wood et al.

    The genetics of chronic obstructive pulmonary disease

    Respir Res

    (2006)
  • VG Cheung et al.

    Natural variation in human gene expression assessed in lymphoblastoid cells

    Nat Genet

    (2003)
  • VG Cheung et al.

    Mapping determinants of human gene expression by regional and genome-wide association

    Nature

    (2005)
  • RS Spielman et al.

    Common genetic variants account for differences in gene expression among ethnic groups

    Nat Genet

    (2007)
  • NR Hackett et al.

    Variability of antioxidant-related gene expression in the airway epithelium of cigarette smokers

    Am J Respir Cell Mol Biol

    (2003)
  • BG Harvey et al.

    Modification of gene expression of the small airway epithelium in response to cigarette smoking

    J Mol Med

    (2007)
  • A Spira et al.

    Effects of cigarette smoke on the human airway epithelial cell transcriptome

    Proc Natl Acad Sci U S A

    (2004)
  • JC Hogg et al.

    Site and nature of airway obstruction in chronic obstructive lung disease

    N Engl J Med

    (1968)
  • Cited by (0)

    These studies were supported in part by R01 HL074326; U01-HL084936; GCRC M01RR00047; and the Rogers Memorial Fund, Los Angeles, CA.

    No conflicts of interest exist for any of the authors.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.html).

    View full text