Genotypes and haplotypes of ERCC1 and ERCC2/XPD genes predict levels of benzo[a]pyrene diol epoxide-induced DNA adducts in cultured primary lymphocytes from healthy individuals: a genotype-phenotype correlation analysis.
Benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts are a risk factor for tobacco-related cancers. Excision repair cross-complementing complementation group 1 (ERCC1) and excision repair cross-complementing complementation group 2/xeroderma pigmentosum D (ERCC2/XPD) participate in the nucleotide excision repair (NER) pathway that removes BPDE-DNA adducts; however, few studies have provided population-based evidence for this association. Therefore, we assayed for levels of in vitro BPDE-induced DNA adducts and genotypes of single-nucleotide polymorphisms (SNPs) of the NER genes ERCC1 (rs3212986 and rs11615) and ERCC2/XPD (rs13181, rs1799793 and rs238406) in 707 healthy non-Hispanic whites. The linear trend test of increased adduct values in never to former to current smokers was statistically significant (P(trend) = 0.0107). The median DNA adduct levels for the ERCC2 rs1799793 GG, GA and AA genotypes were 23, 29 and 30, respectively (P(trend) = 0.057), but this trend was not observed for other SNPs. After adjustment for covariates, adduct values larger than the median value were significantly associated with the genotypes ERCC1 rs3212986TT [odds ratio (OR) = 1.89, 95% confidence interval (CI) = 1.03-3.48] and ERCC2/XPD rs238406AA (OR = 0.64, 95% CI = 0.41-0.99) and rs238406CA (OR = 0.63, 95% CI = 0.45-0.89) compared with their corresponding wild-type homozygous genotypes. The results of haplotype analysis further suggested that haplotypes CAC and CGA of ERCC2/XPD, TC of ERCC1 and CACTC of ERCC2/XPD and ERCC1 were significantly associated with high levels of DNA adducts compared with their most common haplotypes. Our findings suggest that the genotypes and haplotypes of ERCC1 and ERCC2/XPD may have an effect on in vitro BPDE-induced DNA adduct levels.
Zhao
Hui
H
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Wang
Li-E
LE
Li
Donghui
D
Chamberlain
Robert M
RM
Sturgis
Erich M
EM
Wei
Qingyi
Q
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000502:physiology*; D010641:Phenotype; D012016:Reference Values; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
D018736:DNA Adducts; D004268:DNA-Binding Proteins; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human