Variability in small airway epithelial gene expression among normal smokers.
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.
Ammous
Zeinab
Z
Weill Cornell Medical College in Qatar, Education City, Doha, Qatar.
Hackett
Neil R
NR
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY.
Butler
Marcus W
MW
Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY.
Raman
Tina
T
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY.
Dolgalev
Igor
I
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY.
O'Connor
Timothy P
TP
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY.
Harvey
Ben-Gary
BG
Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY.
Crystal
Ronald G
RG
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY. Electronic address: geneticmedicine@med.cornell.edu.
D000328:Adult; D000704:Analysis of Variance; D001999:Bronchoscopy; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics*; D012129:Respiratory Function Tests; D020545:Respiratory Mucosa / Q000473:pathology*; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*