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Potential mechanisms for the decreased expression of the CYP2A13 7520C>G variant allele

Wadsworth Center, NYS Department of Health, School of Public Health, SUNY at Albany, Empire State Plaza, Albany, NY, 12201-0509

ABSTRACT

Our aim was to identify genetic polymorphisms and epigenetic factors that influence CYP2A13 expression. CYP2A13, expressed mainly in the respiratory tract, is highly efficient in the metabolic activation of tobacco-specific nitrosamines. Large interindividual differences exist in the expression of CYP2A13, which likely contribute to the differing susceptibility to lung cancer among smokers. A common 7520C>G variation in CYP2A13 was recently found to be associated with decreased allelic expression in human lung. In vitro data indicated that this SNP, located in the 3'-untranslated region, does not cause changes in the stability of the CYP2A13 transcript. Furthermore, the decreased CYP2A13 expression appeared to be manifest at the transcriptional level. Thus, we also explored possible roles of CYP2A13 promoter region DNA methylation in the decreased expression of the 7520G allele. An allele-specific CpG site, at –1479, which is associated with 7520G, was found to be methylated, for the most part, in human lung DNA samples. Gel shift assays detected specific binding of proteins to the –1479C variant probe, but not to the –1479T "wild-type" probe. Reporter gene assays demonstrated a small, but significant, decrease in CYP2A13 promoter activity associated with the -1479T>C variation. These findings provide the basis for further studies of the mechanisms of regulation of CYP2A13 expression, and for identification of genetic markers for lung adenocarcinoma susceptibility.

(Supported in part by NIH grant CA092596)

This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wu, H. Articles by Ding, X. PubMed Articles by Wu, H. Articles by Ding, X.