Cancer Risk Factor Branch, Cancer Prevention and Research Institute, Florence, Italy.
Mutagenesis. 2013 Jan;28(1):57-63. doi: 10.1093/mutage/ges053. Epub 2012 Sep 17.
The Map-Ta-Phut Industrial Estate (MIE) in Rayong, Thailand, is the location of one of the largest industrial complexes in southeastern Asia. The MIE complex produces a mixture of air pollutants, including polycyclic aromatic hydrocarbons, compounds capable to induce the generation of DNA adducts. DNA adducts are considered to be a biomarker of carcinogen exposure; however, its production can be modulated by genetic susceptibility. Thus, we analysed the influence of EPHX1 His139Arg (A>G, rs2234922) and NQO1 Pro187Ser (C>T, rs1800566) involved in the metabolism of polycyclic aromatic hydrocarbons; MnSOD(2) Val16Ala (C>T, rs1799725) a gene that acts against the free radical generation; APE1/Ref-1 Asp148Glu (T>G, rs3136820) a gene involved in the repair of DNA, and in the control of cell-cycle and apoptosis on leucocyte DNA adducts in 77 MIE workers, 69 Map-Ta-Phut residents, and 50 rural controls, Rayong, Thailand. We searched for associations with the 'sum of at-risk alleles' by combining the variant alleles of EPHX1, NQO1 and MnSOD(2) together with the wild-type allele of APE1, since they appeared to influence lung cancer risk. Although our findings revealed significant associations between DNA adducts and the EPHX1 His139Arg and NQO1 Pro187Ser polymorphisms, the combination of at-risk alleles was found to affect DNA damage much stronger. DNA adducts were significantly increased in the individuals bearing 4 and ≥ 5 at-risk alleles [mean ratio (MR) = 1.55, 95% CI 1.10-2.18, P = 0.012, and MR = 2.11, 95% CI 1.27-3.51, P = 0.004, respectively)]. After correction for residence/employment categorisation, a significant increment was present in the MIE workers with ≥ 5 alleles (MR = 2.88, 95% CI 1.46-5.71, P = 0.003). Our data indicate relationships between the generation of DNA adducts and the enzymatic activities of EPHX and NQO1. The combination of unfavourable genetic variants seems to determine the individuals' susceptibility, rather than a single polymorphism.
泰国罗勇府的玛塔卜工业区（MIE）是东南亚最大的工业综合体之一。该工业区生产多种空气污染物，包括多环芳烃，这些化合物能够诱导 DNA 加合物的产生。DNA 加合物被认为是致癌物暴露的生物标志物；然而，其产生可以通过遗传易感性进行调节。因此，我们分析了多环芳烃代谢相关的 EPHX1 His139Arg（A>G，rs2234922）和 NQO1 Pro187Ser（C>T，rs1800566）、MnSOD(2) Val16Ala（C>T，rs1799725）、APE1/Ref-1 Asp148Glu（T>G，rs3136820）这三个基因的影响，这些基因分别参与自由基的产生、DNA 的修复以及细胞周期和细胞凋亡的控制。在 77 名 MIE 工人、69 名玛塔卜居民和 50 名农村对照组中，我们检测了白细胞 DNA 加合物中与 EPHX1、NQO1 和 MnSOD(2)基因相关的多态性，以及与 APE1 基因野生型等位基因组合的风险等位基因的总和对 DNA 加合物的影响，因为这些等位基因似乎影响肺癌的风险。尽管我们的研究结果显示 DNA 加合物与 EPHX1 His139Arg 和 NQO1 Pro187Ser 多态性之间存在显著相关性，但风险等位基因的组合对 DNA 损伤的影响要强得多。携带 4 个及以上风险等位基因的个体的 DNA 加合物显著增加[比值比（MR）=1.55，95%置信区间（CI）为 1.10-2.18，P=0.012，和 MR=2.11，95%CI 为 1.27-3.51，P=0.004]。在校正居住/就业分类后，MIE 工人中≥5 个等位基因的比例显著增加（MR=2.88，95%CI 为 1.46-5.71，P=0.003）。我们的数据表明，DNA 加合物的产生与 EPHX 和 NQO1 的酶活性之间存在关系。不利遗传变异的组合似乎决定了个体的易感性，而不是单一的多态性。
