title: Genetic polymorphisms in DNA double-strand break repair genes XRCC5, XRCC6 and susceptibility to hepatocellular carcinoma.
abstract: Environmental risk factors cause DNA damages. Imprecise DNA repair leads to chromosome aberrations, genome destabilization and hepatocarcinogenesis. Ku is a key DNA double-strand break repair protein. We hypothesized that the genetic variants in Ku subunits encoding genes, XRCC5/XRCC6, may contribute to hepatocellular carcinoma (HCC) susceptibility. We genotyped 13 common single nucleotide polymorphisms (SNPs) in XRCC5 and XRCC6 and evaluated their associations with HCC risk in 689 pathologically confirmed cases and 690 cancer-free controls from a Chinese population. We found that a significantly reduced risk for HCC was associated with XRCC5 rs16855458 [odds ratio (OR)=0.59; 95% confidence interval (CI)=0.43-0.81; CA+AA versus CC] and a significantly increased risk for HCC was associated with XRCC5 rs9288516 (OR=2.02; 95% CI=1.42-2.86; TA+AA versus TT) even after Bonferroni correction (Pcorrected=0.026 and 0.002, respectively). The effects of rs16855458 (OR=0.57; 95% CI=0.37-0.86, P=0.008) and rs9288516 (OR=1.86; 95% CI=1.19-2.90, P=0.007) were more significant in hepatitis B surface antigen-infected subjects than non-infected subjects. The haplotype-based analysis revealed that in XRCC5, AA in block 1 (OR=0.63; 95% CI=0.48-0.83) and CGGTT in block 2 (OR=0.52; 95% CI=0.39-0.69) were associated with decreased HCC risk (Pcorrected=0.013 and <0.001, respectively). The aforementioned two SNPs exhibited a significant cumulative risk effect (Ptrend<0.001). Additionally, potential interaction among XRCC5 rs9288516 and rs2267437, rs5751131 in XRCC6 was indicated by the multifactor dimensionality reduction analysis. In conclusion, XRCC5 variants may play a role in determining individual's HCC susceptibility, which warranted validation in larger studies.
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433 China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: An
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhou
authors.forename: Ji
authors.initials: J
authors.lastname: Qian
authors.forename: Yin Yao
authors.initials: YY
authors.lastname: Shugart
mesh_terms: D000328:Adult; D000368:Aged; D034961:Antigens, Nuclear / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D000072200:Ku Autoantigen; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen