| Background:Chronic hepatitis B virus(HBV) infection is a major public problem not only in China but also around the world. There are about 350 million to 400 million hepatitis B virus carriers in the world, and Chinese people take apart of about 1/3, nearly 93 million people, which makes our country with the largest amount of chronic hepatitis B virus infectors. Chronic hepatitis B virus infection could cause kinds of severe liver diseases, such as liver cirrhosis(LC), hepatocellular carcinoma(HCC), and so on. Currently, people died of HBV-related liver disease or HCC are about 1 million per year, considerable financial sources and manual labor from lots of countries are invested to investigate this virus, but the mechanisms of HBV-related HCC are still not clear, neither the treatments. HBV Basal Core Promoter region(Enhancer II/BCP/PC) and pre S region mutations are certificated as one of the important reasons for HCC; besides, high serum viral load, genotype C HBV and serum positive of HBe Ag could also increase the risks of HCC. People infecting with HBV in China are much more than other countries indicate that genetic factors play important roles in HCC; the infected individuals are distributed in different regions in China indicate that environmental factors are also the causes of HCC. Human leukocyte antigen(HLA)-DQ antigens are encoded by the human major histocompatibility complex(MHC) II. They play key roles in immune responses, and can be responsible for antigen presentations. Chronic HBV infection may activate immune system by inducing unregulated inflammation in cell microenvironment; whereas, the virus itself can also adaptively evolve under the pressures of immune selection, and in turn promoting the generation of malignant cells. In hence, it’s really necessary to analyze the associations of HLA-DQ genetic polymorphism, HBV mutations and HBV-related diseases, with the purpose of better understanding the mechanisms of HBV-induced liver diseases.Objective:To analyze if single nucleotide polymorphisms(SNPs) of HLA-DQ(rs2856718, rs9275319) are associated with hepatitis B virus-related diseases including hepatitis B virus natural clearance subjects, asymoptomize carriers, chronic hepatitis B virus patients, liver cirrhosis patients and hepatocellular carcinoma patients. Furthermore, we also try to evaluate the correlations of HLA-DQ SNPs and liver diseases, HBV mutations and liver diseases, HLA-DQ SNPs and the frequency of HBV mutations, and the multiple interactions of HLA-DQ SNPs and HBV mutations on end-stage liver diseases.Methods:1342 healthy controls, 327 HBV natural clearance subjects, 611 asymptomatic HBs Ag carriers(ASCs), 1144 chronic hepatitis B virus(CHB) patients, 734 liver cirrhosis(LC) patients and 1531 HCC patients were enrolled in this study. Fluorescent probe real-time quantitative PCR was used for SNP genotyping; nested-PCR was utilized to genotype HBV mutations including HBV pre S region and Enh II/BCP/PC region mutations; MEGA5.0 was used to align HBV DNA and select the liver diseases-related HBV mutations. The associations of HLA-DQ SNPs, HBV mutations and HBV-related liver diseases were analyzed by an unconditional logistic regression model.Results:1. Associations of HLA-DQ SNPs and healthy controls, HBV natural clearance subjects and HBV-related diseases(1) Associations of HLA-DQ SNPs and chronic HBV infectors, HBV natural clearance subjectsAll the data were analyzed by adjusting age and gender, HLA-DQ SNPs(rs2856718 and rs9275319) AG genotype and AG+GG genotype could reduce the risk of chronic HBV infection compared with healthy controls(rs2856718 AG:AOR=0.81,95% CI=0.69-0.95,P=0.009;AG+GG:AOR=0.83,95% CI=0.71-0.96,P=0.015;rs9275319 AG:AOR=0.69,95% CI=0.58-0.83,P=4.56×10-5;AG+GG:AOR=0.70,95% CI=0.59-0.84,P=5.87×10-5); when compared to HBV natural clearance subjects, AG genotype and G allele(AG+GG) of rs9275319 could increase the risks the HBV natural clearances(AG:AOR=0.63,95% CI=0.47-0.85,P=0.003;AG+GG:AOR=0.65,95% CI=0.48-0.87,P=0.003), these significant index could be also found in the stratifications of males and genotype C HBV infectors. When compared with HBV natural clearances, no significances were found in rs2856718.(2) Associations of HLA-DQ SNPs and the progression of end-stage liver diseasesrs2856718 GG genotype and G allele(AG+GG) were associated with the increased risks of LC compared with ASCs and CHB patients(GG: OR=1.52, 95% CI=1.17-1.97, P=0.002; AG+GG: OR=1.27, 95% CI=1.04-1.54, P=0.017), and the variant genotypes of rs2856718 could decrease the risks of HCC compared with healthy controls, chronic HBV infectors and liver cirrhosis patients. After stratifying by HBV genotype, similar results could also be defined in the genotype B/C HBV-infected subjects; after stratifying by gender, the effects of decreased risks of HCC compared to control groups are more significant in males than females. For rs9275319, we could only find that the AG genotype and G allele(AG+GG) were associated with decreased risks of HCC compared with healthy controls(AG, AOR=0.68, 95%CI=0.57-0.82, P=5.76×10-5; AG+GG, AOR=0.70, 95%CI=0.58-0.84, P=9.49×10-5). After stratifying by the gender and HBV genotype, we could only found the similar decisions in males and genotype C HBV-infected subjects, not in the female patients or the genotype B HBV-infected subjects.2. Associations of HLA-DQ SNPs and the frequency of HBV mutationsIn the genotype C HBV-infected subjects, the AG genotype and AG+GG genotype of rs2856718 could increase the frequency of A1726 C mutation(increase the risks of LC and decrease the risks of HCC); rs9275319 GG genotype could increase the frequency of pres1 start codon mutation. In the genotype B HBV-infected subjects, no significance could be found about the associations of HLA-DQ SNPs and the frequency of HBV mutations.3. Interactions of HLA-DQ SNPs and HBV mutations on the end-stage liver diseases(1) Interactions of HLA-DQ SNPs and HBV mutations on LCIn genotype B HBV-infected subjects, interactions of rs2856718 AG+GG genotype and G1652A(LC-risked HBV mutation) had been detected(AOR=6.28,95% CI=1.14-34.59,P=0.035),which played an increased risks of LC. While in genotype C HBV infected subjects, interactions between rs2856718 AG+GG genotype and T1753V(LC-risked HBV mutation) could decrease the risks of LC(AOR=0.26,95% CI=0.09-0.78,P=0.016).(2) Interactions of HLA-DQ SNPs and HBV mutations on HCCIn genotype C HBV infected subjects, interactions between rs2856718 AG genotype and C1673T(HCC-related HBV mutation) could increase the risk of HCC(AOR=2.80, 95% CI=1.02-7.66, P=0.045); interactions of rs2856718 G allele and A1846T (HCC-risked HBV mutation) were discovered, and functioned as a protective factor for the occurrence of HCC(AOR=0.53, 95% CI=0.29-0.98, P=0.042). in genotype B HBV-infected subjects, interactions of rs2856718 genotype AG+GG and T1673C(HCC-related HBV mutation) could decrease the risk of HCC(AOR=0.25, 95% CI=0.07-0.93, P=0.039).Conclusion:1. Variant genotypes of rs2856718 could decrease the risks of HBV chronic infection; the AG genotype and the AG+GG genotype could promote the risks of the development of chronic hepatitis to liver cirrhosis, and decrease the occurrence of HCC.2. HLA-DQ SNP rs9275319 could increase the natural clearance of HBV, and decrease the risk of HCC;3. The associations of HLA-DQ SNPs and HBV-related diseases were more significant in genotype C HBV infectors than genotype B HBV infectors, more significant in males than females.4. HLA-DQ SNPs could influence the frequency of HBV DNA mutations, and complex interactions of them could be found in the progression of HBV-related LC and HCC. |
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