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Potential mechanisms for the decreased expression of the CYP2A13 7520C>G variant allele
Author(s) -
Wu Hong,
Zhang Xiuling,
Ling Guoyu,
D’Agostino Jaime,
Ding Xinxin
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1181-c
Subject(s) - allele , biology , dna methylation , epigenetics , genetics , gene , cpg site , microbiology and biotechnology , methylation , gene expression
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)