Abstract
The glutathione S-transferase (GST) enzymes catalyse the conjugation of xenobiotics to glutathione. Based on reports that inherited copy number variations (CNVs) modulate some GST gene expression levels, and that the small airway epithelium (SAE) and alveolar macrophages (AMs) are involved early in the pathogenesis of smoking-induced lung disease, we asked: do germline CNVs modulate GST expression levels in SAE and AMs? Microarrays were used to survey GST gene expression and determine CNVs genotypes in SAE and AMs obtained by bronchoscopy from current smokers and nonsmokers. 26% of subjects were null for both GSTM1 alleles, with reduced GSTM1 mRNA levels seen in both SAE and AMs. 30% of subjects had homozygous deletions of GSTT1, with reduced mRNA levels in both tissues. Interestingly, GSTT2B exhibited homozygous deletion in the blood of 27% of subjects and was not expressed in SAE in the remainder of subjects, but was expressed in AMs of heterozygotes and wild-type subjects, proportionate to genotype. These data show a germline CNV-mediated linear relationship of genotype with expression level, suggesting minimal compensation of gene expression levels in heterozygotes, consistent with GST polymorphisms playing a role in the risk of smoking-associated, xenobiotic-induced lung disease.
Highlights
26% of subjects were null for both GSTM1 alleles, with reduced GSTM1 mRNA levels seen in both small airway epithelium (SAE) and alveolar macrophages (AMs). 30% of subjects had homozygous deletions of GSTT1, with reduced mRNA levels in both tissues
Based on the knowledge that some members of the glutathione S-transferase (GST) family have a high frequency of gene deletion mediated by germline copy number variations (CNVs) polymorphisms
Subtypes? Through the use of microarray analyses, the data demonstrate that GSTM1 and GSTT1 are expressed in both
Summary
26% of subjects were null for both GSTM1 alleles, with reduced GSTM1 mRNA levels seen in both SAE and AMs. 30% of subjects had homozygous deletions of GSTT1, with reduced mRNA levels in both tissues. GSTT2B exhibited homozygous deletion in the blood of 27% of subjects and was not expressed in SAE in the remainder of subjects, but was expressed in AMs of heterozygotes and wild-type subjects, proportionate to genotype. These data show a germline CNV-mediated linear relationship of genotype with expression level, suggesting minimal compensation of gene expression levels in heterozygotes, consistent with GST polymorphisms playing a role in the risk of smoking-associated, xenobiotic-induced lung disease. CORRESPONDENCE R.G. Crystal Dept of Genetic Medicine Weill Cornell Medical College 1300 York Avenue Box 96 New York NY 10065 USA E-mail: geneticmedicine@ med.cornell.edu. Accepted after revision: The epithelial surfaces of cigarette smokers are exposed to large amounts of inhaled compounds in an aerosol of 1014 free radicals per puff, 1010 particulates?mL-1 and .4,000
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