XRCC1, XRCC3, XPD gene polymorphisms, smoking and P-32-DNA adducts in a sample of healthy subjects

DNA repair genes have an important role in protecting individuals from canc er-causing agents. Polymorphisms in several DNA repair genes have been iden tified and individuals with non-dramatic reductions in the capacity to repa ir DNA damage are observed in the population, but the impact of specific ge netic variants on repair phenotype and cancer risk has not yet been clarifi ed. In 308 healthy Italian individuals belonging to the prospective Europea n project EPIC, we have investigated the relationship between DNA damage, a s measured by P-32-DNA adduct levels, and three genetic polymorphisms in di fferent repair genes: XRCC1-Arg399Gln (exon 10), XRCC3-Thr241Met (exon 7) a nd VPD-Lys751Gln (exon 23). DNA adduct levels were measured as relative add uct level (RAL) per 10(9) normal nucleotides by DNA P-32-post-labelling ass ay in white blood cells from peripheral blood. Genotyping was performed by PCR-RFLP analysis. The XRCC3-241Met variant was significantly associated wi th higher DNA adduct levels, whereas XRCC1-399Gln and XPD-751Gln were assoc iated with higher DNA adduct levels only in never-smokers. XRCC3-241Met hom ozygotes had an average DNA adduct level of 11.44 +/-1.48 (+/- SE) compared with 7.69 +/-0.88 in Thr/Met heterozygotes and 6.94 +/-1.11 in Thr/Thr hom ozygotes (F=3.206, P=0.042). Never-smoking XRCC1-399Gln homozygotes had an average DNA adduct level of 15.60 +/-5.42 compared with 6.16 +/-0.97 in Gln /Arg heterozygotes and 6.78 +/-1.10 in Arg/Arg homozygotes (F=5.237, P=0.00 7). A significant odds ratio (3.81, 95% CI 1.02-14.16) to have DNA adduct l evels above median value was observed for XPD-751Gln versus XPD-751Lys neve r-smoking homozygotes after adjustment for several confounders. These data show that all the analysed polymorphisms could result in deficient DNA repa ir and suggest a need for further investigation into the possible interacti ons between these polymorphisms, smoking and other risk factors.