| The hepatitis B virus infection(HBV)is a prevalent type of infectious disease that is causing a global concern for public health.Although there has been considerable improvement in understanding the molecular virology and pathogenesis of the HBV infection over the past decade and effective therapeutic measures have been developed for its treatment,there are currently 240 million individuals globally who are chronic HBV carriers,and 620,000 succumb per year due to late sequelae of liver cirrhosis or hepatocellular carci-noma(HCC).In our country,the hepatitis b surface antigen rate is up to 7.18%,that is to say,about 90 million people are chronic HBV carriers.About 200,000 people died annually from liver disease after HBV infection.There are significant differences in the prognosis of patients with HBV infection,genetic and environmental factors are involved in the vulnerability to HBV infection and liver disease progress.APOBEC3s are members of the cytosine deaminase family,which are important innate immune molecules in human and play an important role in the process of antiretroviral.For HBV DNA replication has reverse transcription process,therefore,APOBEC3s also have the inhibitory effect on hepatitis B virus.On one hand,the APOBEC3s inhibit HBV by editing the viral DNA cytosine into uracil,then part of the virus DNA are identified by uracil DNA glycosylases inducing the degradation of DNA,and also APOBEC3 inhibite the viral replication stage and promote the degradation of HBV DNA.On the other hand,mild editing may lead to the escape of the virus and variations.Studies confirmed that the APOBEC3 family members all can significantly inhibit HBV DNA.Recent research showed that APOBEC3A and APOBEC3B are essential for cccDNA degradation by IFN-??IFN-??TNF-? and the lymphotoxin-? receptor-agonist.So we designed the clinical case-control study to make certain of the relationship between APOBEC3 gene polymorphism and HBV susceptibility,liver disease progression,the occurrence and prognosis of HCC.We wonder to find a new biological marker and effectively target molecules in inhibiting HBV DNA and/or even clearing cccDNA.This study is divided into the following three parts.(1)Association between polymorphisms of the APOBEC3G gene and chronic hepatitis B viral infection and hepatitis B virusrelated hepatocellular carcinomaAIM:We have chosen five APOBEC3G single nucleotide polymorphisms(SNPs):rs7291971?rs5757465?rs5757463?rs8177832?rs2011861.The case-control study help us to determine the relationship between five APOBEC3G SNPs and the susceptibility of hepatitis B virus(HBV)infection and HCC.METHODS:This association study was designed as a retrospective study,including 657 patients with chronic HBV infection and 299 healthy controls.All subjects were ethnic Han Chinese.Chronic HBV-infected patients recruited between 2012 and 2015 at The First Hospital of Jilin University(Changchun)were further classified into HBV-related HCC patients(N = 287)and Non-HCC patients(N = 370)(104 chronic hepatits B patients and 266 liver cirrhosis patients).Frequency matching by age and sex was performed for each group.Human genomic DNA was extracted from whole blood.Gene polymorphisms were identified using a mass spectroscopic method.Then the haplotype distribution frequency in each group is analysed.Through analyzing the association of SNP genotype and the correlation of serum viral load and e antigen seroconversion to clear how SNPs act on the HBV susceptibility and HCC occurrence.RESULTS:There were no significant association between the genotype and allele frequencies of the APOBEC3G rs7291971,rs5757465,rs5757463 and the risk of chronic hepatitis B virus infection and HBV-related HCC.The G allele for rs8177832 were significantly related to a decreased risk of chronic hepatitis B virus infection(OR = 0.69,95%CI:0.50-0.95).Compared to AA genotype,AG genotype and AG plus GG were significantly related to a decreased risk of chronic hepatitis B infection(OR = 0.67,95%CI:0.47-0.96;OR = 0.66,95%CI:0.47-0.94,respectively).Similarly,compared to A allele,G allele were significantly related to a decreased risk of hepatocellular carcinoma(OR =0.58,95%CI:0.39-0.87).Compared to AA genotype,AG genotype and AG plus GG were significantly related to a decreased risk of hepatocellular carcinoma(OR = 0.53,95%Cl:0.33-0.84;OR = 0.54,95%CI:0.35-0.85).A significant relationship was found between rs2011861 CT,TT,CT plus TT genotypes and increased risk of HCC(OR = 1.69,95%CI:1.02-2.80;OR = 1.82,95%CI:1.08-3.06,OR = 1.75,95%CI:1.08-2.82,respectively).Haplotype analyses showed thatrs5757463-rs8177832 C-G allele,compared to wild type C-A,was associated with low risk of chronic hepatitis B infection(OR = 0.71;95%CI:0.51-0.98).Compared to wild type,rs7291971-rs8177832 G-G allele(OR = 0.61;95%CI:0.39-0.95).rs5757463-rs8177832 C-G allele(OR = 0.61;95%CI:0.40-0.91)?rs5757465-rs8177832 T-G allele(OR = 0.58;95%CI:0.38-0.88)were related to low risk of HCC.Oppositely,compared to wild type,rs5757463-rs2011861 C-T.G-C allele(OR = 1.41,95%CI:1.08-1.83;OR = 1.80,45%CT:1.15-2182)?rs7291971-rs5757463-rs8177832 C-G-A allele(OR = 1.64,95%Cl:1.03-2.61)?rs7291971-rs5757463-rs2011861 C-G-C allele(OR = 1.70,95%CI:1.05-2.76)had significantly high risk of HCC occurrence.Then we analyzed the association between rs8177832?rs2011861 genotype and hepatitis B viral load,Hepatitis B e antigen seroconversion.The results shows that the viral load of rs8177832 GG genotype is lower than AA genotype in Non-HCC group(P = 0.043,OR = 1.69,95%Cl:1.27-1.27),But there were no difference of the viral load between the APOBEC3G different genotypes in other two groups(HCC group,Chronic hepatitis B infection group).There were no difference of the viral load of rs2011861 three genotypes in the three group(Non-HCC group,HCC group,Chronic hepatitis B infection group).Similarly,the results shows that the seroconversion rate of hepatitis e antigen in rs8177832 AG,AG plus GG genotype was higher than AA genotype in Non-HCC group(P = 0.02,P =0.02).In chronic hepatitis B infection group,the seroconversion rate of hepatitis e antigen in rs8177832 AG,AG plus GG genotype proned to be higher than AA genotype(P = 0.07,P =0.07).But there was no difference of the HBeAg(+)HBeAb(-)/HBeAg(-)HBeAb(+)in rs8177832 different genotypes in HCC group.Also,there were no difference of e antigen seroconversion rate of rs2011861 three genotypes in the three groups(Non-HCC group,HCC group,Chronic hepatitis B infection group).(2)Association between polymorphisms of the APOBEC3A?APOBEC3B?APOBEC3H gene and hepatitis B progression and hepatocellular carcinoma occurrenceAIM:We have chosen 10 APOBEC3 SNPs:rs7286317?rs7290153 of APOBEC3A,rs2267398?rs2267401?rs2076109 of APOBEC3B,rs56695217?rs139292?rs139297?rs139302?rsl39316 of APOBEC3H.The case-control study help us to determine the relationship between APOBEC3 SNPs and the progression of hepatitis B and occurrence of HCC.METHODS:This association study was designed as a retrospective study,including 653 patients with chronic HBV infection.Chronic HBV infection patients were further classified into chronic hepatitis B patients(N=104),liver cirrhosis patients(N=265),HBV-related HCC patients(HCC)(N = 285).Gene polymorphisms were identified using a mass spectroscopic method.RESULTS:There were no difference distribution between rs7286317?rs7290153 of APOBEC3A,rs2267398?rs2267401?rs2076109 of APOBEC3B,rs56695217?rs139292?rs139297?rs/139302?rs/139316 of APOBEC3H genotypes and alleles in each group.Haplotype analyses showed that there were no significant difference between allele distribution of APOBEC3A and APOBEC3B in each group.But the distribution of APOBEC3B rs2267398-rs2267401-rs2076109 between liver cirrhosis group and HCC group had statistic difference,the mutants C-T-A?C-T-G?T-G-G?T-T-G have low risk of HCC occurrence compared to wild type(OR = 0.19,95%C1:0.07-0.53;OR = 0.16,95%C1:0.06-0.45;OR = 0.18,95%Cl:0.07-0.49;OR = 0.07,95%Cl:0.01-0.38).(3)Association between APOBEC3B deletion polymorphism and susceptibility to chronic hepatitis B infection and outcomes of hepatocellular carcinomaAIM:To investigate the association of APOBEC3B deletion with susceptibility to chronic hepatitis B virus infection and occurrence,prognosis of HCC.METHODS:In this retrospective case-control study,a total of 654 patients with chronic HBV infection and 249 healthy controls were recruited.The chronic HBV infection patients included 104 chronic hepatitis B patients,263 liver cirrhosis patients and 287 HCC patients.The APOBEC3B intact(I)and deletion(D)alleles were genotyped using polymerase chain reaction(PCR)method.Totally 243 HCC patients was followed-up and their clinicopathologic characteristics was collected.RESULTS:Compared to healty control group,there were no significant difference in the distribution of APOBEC3B genotypes and alleles in Non-HCC group,chronic hepatitis B infection group.Compared with the II genotype,the DD genotype was significantly related to a increased risk of HCC after adjusting for age,sex,smoking,and drinking(OR = 1.95,95%CI:1.03-3.69).No significant differences were found in the frequencies of genotype and alleles of APOBEC3B deletion among HBV infection patients(hepatitis B patients,liver cirrhosis patients,and HCC).No significant differences were found between the overall survival of the APOBEC3B deletion genotypes.Above all,we get the following conclusion:(1)APOBEC3G rs8177832 AG genotype and G allele reduced the risk of chronic hepatitis B infection and HCC,may due to enhanced inhibiting action of APOBEC3G on HBV viral load and accelerated e antigen seroconversion.Rs2011861 CT?TT genotypes related to higher risk of HCC.(2)Rs7286317?rs7290153 of APOBEC3A,rs2267398?rs2267401?rs2076109 of APOBEC3B?rs56695217?rs139292?rs139297?rs139302?rs139316 of APOBEC3H have no correlation with chronic hepatits B progression and HCC occurrence.(3)APOBEC3B deletion related to higher risk of HCC,but not susceptibility of chronic HBV infection and progression of hepatitis B.APOBEC3B deletion has no significant influence on the over-all survival of HCC. |
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