Correlation between Base-Excision Repair Gene Polymorphisms and Levels of In-Vitro BPDE–Induced DNA Adducts in Cultured Peripheral Blood Lymphocytes

• Published in: PloS one Vol. 7; no. 7; p. e40131
• Main Authors: Yu, Hongping, Zhao, Hui, Wang, Li-E, Liu, Zhensheng, Li, Donghui, Wei, Qingyi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.07.2012; Public Library of Science (PLoS)
• Subjects: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide - toxicity; Adducts; Adenosine; Adult; Aged; Alleles; Analysis; Benzo(a)pyrene; Benzo(a)pyrene-diol epoxide; Benzopyrene; Biology; Biomarkers; Blood; Cancer; Cancer research; Carcinogens; Cell culture; Cell Line; Cells, Cultured; Deoxyribonucleic acid; DNA; DNA adducts; DNA Adducts - drug effects; DNA Repair; E coli; Enzymes; Epidemiology; Epstein-Barr virus; Escherichia coli; Female; Gene expression; Gene polymorphism; Genes; Genetic aspects; Genetic Association Studies; Genetic polymorphisms; Genotype; Genotypes; Health aspects; Health care; Health risks; Humans; Ionizing radiation; Lymphoblastoid cell lines; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Male; Mammals; Medicine; Middle Aged; Peripheral blood; Phenotypes; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase 1; Polymorphism; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population genetics; Population studies; Proteins; Pyrene; Repair; Risk; Risk reduction; RNA; Smokers; Smoking; Viruses; XRCC1 protein; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040131

In vitro benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts in cultured peripheral lymphocytes have been shown to be a phenotypic biomarker of individual's DNA repair phenotype that is associated with cancer risk. In this study, we explored associations between genotypes of base-excision repair genes (PARP1 Val762Ala, APEX1 Asp148Glu, and XRCC1 Arg399Gln) and in vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes in 706 cancer-free non-Hispanic white subjects. We found that levels of BPDE-induced DNA adducts were significantly higher in ever smokers than in never smokers and that individuals with the Glu variant genotypes (i.e., Asp/Glu and Glu/Glu) exhibited lower levels of BPDE-induced DNA adducts than did individuals with the common Asp/Asp homozygous genotype (median RAL levels: 32.0 for Asp/Asp, 27.0 for Asp/Glu, and 17.0 for Glu/Glu, respectively; P(trend) = 0.030). Further stratified analysis showed that compared with individuals with the common APEX1-148 homozygous Asp/Asp genotype, individuals with the APEX1-148Asp/Glu genotype or the Glu/Glu genotype had a lower risk of having higher-level adducts (adjusted OR = 0.60, 95% CI: 0.36-0.98 and adjusted OR = 0.47, 95% CI: 0.26-0.86, respectively; P(trend) = 0.012) among smokers. Such an effect was not observed in non-smokers. However, there was no significant interaction between the APEX1 Asp148Glu polymorphism and smoking exposure in this study population (P = 0.512). Additional genotype-phenotype analysis found that the APEX1-148Glu allele had significantly increased expression of APEX1 mRNA in 270 Epstein-Barr virus-transformed lymphoblastoid cell lines, which is likely associated with more active repair activity. Our findings suggest that the functional APEX1-148Glu allele is associated with reduced risk of having high levels of BPDE-induced DNA adducts mediated with high levels of mRNA expression.