XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects
XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects
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DOI：
10.1093/carcin/22.9.1437
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发表时间：
2001-09-01
期刊：
影响因子：
4.7
通讯作者：
Vineis, P
中科院分区：
文献类型：
--
作者：
Matullo, G;Palli, D;Vineis, P
DNA修复基因在保护个体免受致癌物质的侵害方面具有重要作用。已经鉴定了几种DNA修复基因的多态性，并且在人群中观察到修复DNA损伤的能力没有显著降低的个体，但是特定遗传变异对修复表型和癌症风险的影响尚未阐明。在308名健康的意大利人属于前瞻性欧洲项目EPIC，我们调查了DNA损伤之间的关系，测量P-32-DNA加合物水平，和三个不同的修复基因的遗传多态性：XRCC 1-Arg 399 Gln（外显子10），XRCC 3-Thr 241 Met（外显子7）和VPD-Lys 751 Gln（外显子23）。通过DNA P-32-后标记测定法，在外周血白色细胞中测量DNA加合物水平，作为每10（9）个正常核苷酸的相对加合物水平（RAL）。采用PCR-RFLP方法进行基因分型。XRCC 3 - 241 Met变异与较高的DNA加合物水平显著相关，而XRCC 1 - 399 Gln和XPD-751 Gln仅在从不吸烟者中与较高的DNA加合物水平相关。XRCC 3 - 241 Met纯合子的平均DNA加合物水平为11.44 ± 1.48（± SE），而Thr/Met杂合子为7.69 ± 0.88，Thr/Thr纯合子为6.94 ± 1.11（F=3.206，P=0.042）。从不吸烟的XRCC 1 - 399 Gln纯合子的平均DNA加合物水平为15.60 +/-5.42，而Gln/Arg杂合子为6.16 +/-0.97，Arg/Arg纯合子为6.78 +/-1.10（F=5.237，P=0.007）。在调整几个混杂因素后，观察到XPD-751 Gln与XPD-751 Lys从不吸烟纯合子的DNA加合物水平高于中位数的显著比值比（3.81，95%CI 1.02-14.16）。这些数据表明，所有分析的多态性可能导致DNA修复缺陷，并建议需要进一步调查这些多态性，吸烟和其他危险因素之间可能的相互作用。
DNA repair genes have an important role in protecting individuals from cancer-causing agents. Polymorphisms in several DNA repair genes have been identified and individuals with non-dramatic reductions in the capacity to repair DNA damage are observed in the population, but the impact of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. In 308 healthy Italian individuals belonging to the prospective European project EPIC, we have investigated the relationship between DNA damage, as measured by P-32-DNA adduct levels, and three genetic polymorphisms in different repair genes: XRCC1-Arg399Gln (exon 10), XRCC3-Thr241Met (exon 7) and VPD-Lys751Gln (exon 23). DNA adduct levels were measured as relative adduct level (RAL) per 10(9) normal nucleotides by DNA P-32-post-labelling assay in white blood cells from peripheral blood. Genotyping was performed by PCR-RFLP analysis. The XRCC3-241Met variant was significantly associated with higher DNA adduct levels, whereas XRCC1-399Gln and XPD-751Gln were associated with higher DNA adduct levels only in never-smokers. XRCC3-241Met homozygotes 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 homozygotes (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=0.007). A significant odds ratio (3.81, 95% CI 1.02-14.16) to have DNA adduct levels above median value was observed for XPD-751Gln versus XPD-751Lys never-smoking homozygotes after adjustment for several confounders. These data show that all the analysed polymorphisms could result in deficient DNA repair and suggest a need for further investigation into the possible interactions between these polymorphisms, smoking and other risk factors.