Single-Nucleotide Polymorphisms In DNA Repair Gene HOGG1 And APE1 And Susceptibility To Hepatocellular Carcinoma

Background and objectivesHepatocellular carcinoma(HCC) is one of the malignant tumors in the world.China is one of countries with high incidence of HCC.Especially,in Guangxi,The incidence rate of HCC is 27.31 per 100000 and HCC is the most commom cancer and the leading cause of death form cancer in Guangxi. Carcinogenesis mechanism of HCC is still not clear.HCC is the result of a combination of environmental factors,genetical factors or both.Previous epidemiological studies have suggested that the major risk factors for HCC are chronic infection with hepatitis B virus(HBV),chronic infection with hepatitis C virus(HCV) and foods contaminated with aflatoxin B₁(AFB₁).Alcohol drinking and cigarette smoking have also been implicated in the etiology of HCC.However,not all the individuals exposed to the risk factors will progress to HCC eventually,which suggests a differential susceptibility to HCC.It is well known that single nucleotide polymorphisms(SNPs) in DNA repair genes modulate the DNA repair capacity and might affect the susceptibility to cancer. Base excision repair(BER) is the primary DNA damage repair mechanism for repairing small base lesions resulting from oxidation and alkylation damage.The current study was to test our hypothesis that SNPs in human 8-oxoguanine glycosylase 1 gene(hOGGl) and apurinic/apyrimidinic endonuclease 1 gene (APEl) contribute to HCC through gene-gene and gene-environment interactions.MethodsThis hospital-based case control study included 500 HCC patients and 507 controls.All patients had newly diagnosed,untreated HCC that was histopathologically confirmed at two main hospitals in Guangxi(the First Affiliated Hospital of Guangxi Medical University and the First Affiliated Hospital of Guangxi Traditional Chinese Medicine University) between June 2007 and December 2008.Cancer-free control subjects were recruited from the above hospitals at the same period.The control subjects were frequencily matched by sex,age(±5 years) and residential area.We surveyed all study subjects by using a questionnaire to obtain demographic information.Four milliliter peripheral venous blood was drawn from the study subjects.HBsAg, nati-HBs,HBe,nati-HBe,nati-HBc and anti-HCV were measure by Enzyme-linked immunoadsorbent assay(ELISA);hOGGl-Ser326Cys polymorphism and the APEl-Asp148Glu polymorphism were genotyped by a real time polymeras chain reaction-TaqMan MGB.Student's t-test was used to compare mean value of the samples.While categorical data were analyzed by the chi square test and unconditional logistic regression models.The odds ratio (OR) and 95%confidence interval(CI) were used to indicate relative risk to HCC.The gene-gene and gene-environment interaction on HCC risk was evaluated by the crossover analysis.All data were analyzed using the computer software SPSS for windows(version 13.0).Results1.All HCC case patients and control subjects were adequately matched by age,sex,nationality and vocation.2.HBV infection(OR = 9.86,95%CI:6.59-14.76) and drinking(OR = 3.96, 95%CI:2.49-6.30) were the major risk factors for HCC.3.The allele mutation frequencies of hOGGl-326Cys and APEl-148Glu in the control group and case group were 10.75%,6.61%and 24.60%,16.10% respectively,the differences were significant between the two groups(P < 0.05). The genotype frequencies of hOGGl Ser/Ser,Ser/Cys,Cys/Cys were 84.22%, 10.06%,5.72%in controls and 71.40%,8.00%,20.6%in cases respectively,and there were statistical significances between the two groups(P < 0.05);The genotype frequencies of APEl Asp/Asp,Asp/Glu,Glu/Glu were 89.74%,7.30%, 2.96%in controls and 80.40%,7.00%,12.60%in cases respectively,and statistical significances were shown between the two groups(P < 0.05).Heterozygosity for the hOGGl-326Ser/Cys genotype is not associated with the risk of HCC(OR = 1.05,95%CI:0.68-1.34);Homozygous mutue hOGGl-326Cys/Cys genotype significantly increased the risk of HCC(OR = 1.63,95%CI:1.12-2.39),The hOGGl-326Cys/Cys mutant genotype is the risk genotype for HCC.Compared with wild hOGGl-326Ser/Ser genotype,the hOGGl mutant allele increased the risk of HCC(OR = 2.14,95%CI:1.57-2.91). The hOGGl-326Cys allele(adjusted OR = 1.88,95%CI:1.22-5.83) was the significant determinant factor for HCC. Compared with wild APEl-148Asp/Asp genotype,heterozygosity for the APEl-148Asp/Glu genotype increased the risk of HCC(OR = 1.19,95%CI: 0.55-1.98),but no statistical significances were shown between the two genotypes(P > 0.05);Homozygous mutue APEl-148Glu/Glu genotype significantly increased the risk of HCC(OR = 1.56,95%CI:1.04-2.87).The APEl-148Glu/Glu mutant genotype is the risk genotype for HCC.Compared with wild APEl-148Asp/Asp genotype,the APEl-148Glu mutant allele increased the risk of HCC(OR = 2.13,95%CI:1.22-2.89).The APEl-148Glu allele(adjusted OR = 1.74,95%CI:1.09-3.83) was the significant determinant factor for HCC.4.The interaction between hOGGl-326Cys allele and APEl-326Glu allele significantly increased the risk of HCC(OR = 4.03,95%CI:2.07-7.87) and the interaction model was a positive additive model and the AP was 25%.5.The interaction between the hOGGl-326Cys allele and drinking(OR = 8.20,95%CI:2.07-7.87) or the interaction between the hOGGl-326Cys allele and chronic HBV infection(OR = 38.15,95%CI:18.90-61.71) tremendously increased HCC risk.The interaction model for hOGGl-326Cys allele and drinking was a negative multiplicative model,the hOGGl-326Cys allele and chronic HBV infection was an additive interaction(S = 1.31).The interaction between the APEl-148Glu allele and drinking(OR = 7.36, 95%CI:3.51-15.47) or the interaction between the APEl-148Glu allele and chronic HBV infection(OR = 36.73,95%CI:17.82-75.74) tremendously increased HCC risk.The interaction model for APEl-148Glu allele and drinking was a negative multiplicative model,the APEl-148Glu allele and chronic HBV infection was an additive interaction(S = 1.44). ConclusionsChronic HBV infection and drinking were the major risk factors for HCC. The hOGGl-326Cys allele and APEl-148Glu allele may contribute to the risk of HCC in a gene-gene interaction model and modify the risk associated with chronic HBV infection and drinking.