Genetic variants of nucleotide excision repair genes are associated with DNA damage in coke oven workers

Abstract

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 (Ptrend = 0.004). This association was more pronounced in subjects with higher PAH exposure than those with lower exposure levels (Pinteraction = 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. ©2010 AACR.