Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):211-8. doi: 10.1158/1055-9965.EPI-09-0270.
We explored the effects of single nucleotide polymorphisms (SNP) of nucleotide excision repair (NER) genes on DNA damage caused by exposure to carcinogenic polycyclic aromatic hydrocarbons (PAH) in 475 Chinese workers. We quantified urinary 1-hydroxypyrene using high-performance liquid chromatography, and the DNA damage level of lymphocytes was examined by the comet assay and represented as the Olive tail moment (OTM) value. We genotyped 38 tagSNPs in 10 NER genes. The SNP function was further investigated using luciferase reporter assay in three cell lines. Our results showed that two promoter SNPs, XPA rs1800975 and XPC rs3731055, were associated with lower OTM values (P(trend) = 0.01 and 0.02 respectively). However, another missense SNP rs2228001 in the XPC gene was positively associated with OTM value (P(trend) = 0.01). A stratified analysis found that the association between this SNP and DNA damage was only observed among subjects with higher PAH exposure levels but not among those with lower exposure levels (P(interaction) = 0.018). A dose-response association was found between the combined risk alleles of the above three genetic variants and increased DNA damage levels (P(trend) = 0.004). This association was more pronounced in subjects with higher PAH exposure than those with lower exposure levels (P(interaction) = 0.046). Our functional study indicated that XPA rs1800975G and XPC rs3731055A alleles had a higher luciferase expression than their corresponding SNP alleles (P < 0.05). These results suggested that genetic variations in key NER genes, especially in XPA and XPC genes, may modulate DNA damage levels when exposed to PAHs.
我们研究了核苷酸切除修复（NER）基因单核苷酸多态性（SNP）对 475 名中国工人接触致癌多环芳烃（PAH）导致的 DNA 损伤的影响。我们使用高效液相色谱法定量测定尿液中的 1-羟基芘，并用彗星试验检测淋巴细胞的 DNA 损伤水平，并表示为橄榄尾矩（OTM）值。我们对 10 个 NER 基因中的 38 个标签 SNP 进行了基因分型。我们在三个细胞系中使用荧光素酶报告基因检测进一步研究了 SNP 的功能。我们的结果表明，两个启动子 SNP，XPA rs1800975 和 XPC rs3731055，与较低的 OTM 值相关（P（趋势）分别为 0.01 和 0.02）。然而，XPC 基因中的另一个错义 SNP rs2228001 与 OTM 值呈正相关（P（趋势）= 0.01）。分层分析发现，该 SNP 与 DNA 损伤之间的关联仅在 PAH 暴露水平较高的受试者中观察到，而在暴露水平较低的受试者中未观察到（P（交互作用）= 0.018）。在上述三个遗传变异的组合风险等位基因与 DNA 损伤水平增加之间发现了剂量反应关系（P（趋势）= 0.004）。这种关联在 PAH 暴露水平较高的受试者中比暴露水平较低的受试者中更为明显（P（交互作用）= 0.046）。我们的功能研究表明，XPA rs1800975G 和 XPC rs3731055A 等位基因的荧光素酶表达高于相应的 SNP 等位基因（P<0.05）。这些结果表明，关键 NER 基因中的遗传变异，特别是 XPA 和 XPC 基因中的遗传变异，可能在接触 PAHs 时调节 DNA 损伤水平。
