Investigation of the role of alcohol- metabolizing genes and DNA repair genes in the increase of levels of N2-ethylidenedeoxyguanosine

摘要: 1885 Background: Studies have shown a correlation between alcohol drinking and formation of N2-ethylidenedeoxyguanosine (N2-ethylidene-dG), specific acetaldehyde derived DNA adduct. These results contribute to the hypothesis major role in mechanisms related carcinogenesis. Association levels this adduct with ALDH2 genes has also been demonstrated. In study we investigated possible influences on N2-ethylidene-dG variants encoding for enzymes involved ethanol metabolism repair.
 Methods: 127 subjects different habits were selected from controls ARCAGE large multicenter case-control head neck cancers conducted Europe. was measured as its reduced form N2-ethyldG by LC-ESI-MS/MS-SRM, performing enzyme-catalyzed hydrolysis presence NaBH3CN. On same samples, nine polymorphisms four (ADH1B, ADH1C ADH7 ADH4) analysed TaqMan assay 19 12 repair (XRCC1, XRCC2, XRCC3, XRCC9, LIG3, PCNA, MGMT, OGG1, ERCC1, ERCC4, POLB, APEX), APEX. Genes according preliminary data an association cancer susceptibility. The effect SNPs risk having high adducts investigated.
 Results: Levels showed dose response relationship across categories (p = 0.02). No observed when considering metabolism. addition, no these intake detected. Within group analysed, variant alleles XRCC1 gene significant influence N2-ethyldG. When adjusting sex, age, smoking status, increased rs915927 exon 8 (OR 2.54, 95% CI 1.08-5.92, p=0.03) rs762507 intron 5 (OR2.77, 1.16-6.58, p=0.02), while decreased rs25487 10 0.38, 0.16-0.83, p=0.01). combination alleles, more than one allele had 3.9, 1.48-10.48, p=0.006).
 Conclusion: suggest pathway relevant formation. Further studies larger number are needed better understand ADH alone ALDH genes. Additional investigation is focusing synergistic or additive effects involved.