Association Between Immune Function Related Gene Copy Number Variations And Hepatitis B Virus Infection Outcome

BackgroundsHepatitis B viral（HBV）infection has been a serious threat to human health and quality of life,it becomes the world’s important public health problem.The disease spectrum of HBV infection ranges from acute HBV infection to chronic HBV carrier to chronic hepatitis,liver cirrhosis,and HCC.The outcome of HBV infection is not only affected by the virus itself,but also the environmental factors,the host’s immune response,and the interaction of genetic diversity.The differences between the degree of immune response in different host,so host antiviral immunity genetic background difference is one of the important reasons influence after HBV infection disease progression.Current research shows that copy number variation can affect gene expression through the dose effect of gene and structural change,thus affecting the susceptibility and progression of disease.To study the differences in the gene copy number variation of the immune-related factors in different HBV infection groups can further clarify the role of the individual immune genetic background in the process of chronic hepatitis B infection,deepen the understanding of the pathogenesis of hepatitis b,and may also contribute to the prevention and treatment of hepatitis B in the future.AimsIn patients with acute HBV infection recovery and chronic HBV infection as the research object,the two immune-related factors,TLR7and PD-1 were selected to study the differences of the frequency of their copy number in different outcomes in HBV infection.And the correlation between genetic susceptibility to chronic HBV infection are discussed in this paper.Methods1.This study included 623 patients（495 males and 128 females）with chronic hepatitis B virus infection and 300 patients（135 females and 165 males）with acute HBV infection recovery period as controls.All chronic HBV infection patients were further categorized according to disease progression after HBV infection（CHB,liver cirrhosis,or hepatocellular carcinoma）.Copy numbers of the TLR7 gene were measured using the AccuCopy method.χ² tests were used to evaluate the association between TLR7 CNVs and infection type.P values,odds ratios,and 95%confidence intervals（CIs）were used to estimate the effects of risk.2.We collected 809 patients（650 males and 159 females）with chronic hepatitis B virus infection（CHB）and 300 patients（135 females and 165 males）with acute HBV infection recovery as controls.All CHB patients were further categorized according to disease progression after HBV infection（CHB,liver cirrhosis,or hepatocellular carcinoma）.The HBV-DNA was extracted and purified by the above methods,and the number of copies of PD-1 was detected.SPSS software was used to analyze the distribution of pd-1 copies in each group.3.Logistic regression analysis was performed on 5 indicators that may affect the results of chronic HBV infection（e antigenic titer,age,sex,DNA,TLR/PD-1 CNs）,P<0.05indicates statistical difference.Results1.TLR7 CNs were significantly different between the acute and chronic group in both male and female patients（males:χ²=37.682,P<0.001;females:χ²=22.063,P<0.001）.Low copy number of TLR7 was significantly associated with chronic HBV infection（OR=0.329,95%CI:0.229–0.473）.Difference in TLR7 copy number was also found between control group and CHB female patients,with low copy number again associated with an increased risk of chronic HBV infection（OR=0.292,95%CI:0.173–0.492）.2.We also compared the TLR7 CN distributions of the CHB,LC,and HCC groups,but there were no significant differences among the three groups（male:χ²=1.923,P=0.382;female:χ²=1.557,P=0.459）.3.We divided chronic HBV infection patients into two groups according to e-antigen titers（0–1 IU/mL vs>1 IU/mL）.However,titer levels did not vary significantly among patient groups.（male:χ²=0.032,P=0.859;female:χ²=0.185,P=0.667）.4.Through the statistical analysis,we found that acute HBV infection recovery group and LC group were statistically significant in the CNV of the distribution of PD-1 copy number.（χ²=4.473,P=0.034）.5.After the combination of the three groups of chronic hepatitis B infection were combined,the chi-square test was conducted with the acute HBV infection recovery period group,and the results indicated that there was no statistical difference between the frequency of CNV of PD-1（χ²=1.641,P=0.2>0.05）.According to the disease outcomes of chronic HBV infection we divided the patients into three group including chronic hepatitis b,liver cirrhosis and liver cancer group,and we found that there was no statistically significant of the CNV between the three chronic HBV infection（χ²=3.256,P=0.196）.6.The experiment selected 5 factors may have significant association with different outcomes of HBV infection including age,gender,CN of PD-1/TLR7 genes,HBV-DNA,eAg.After multiple factor regression analysis,the CHB group as the control group to estimate the parameters,the factors affecting the prognosis of the disease were age and HBV-DNA.Conclusions1.TLR7 gene copy number variation is associated with the susceptibility of chronic hepatitis b virus.Low TLR7 copy number is a risk factor for chronic HBV infection but is not associated with later stages of disease progression.Patients with low viral loads are more likely to progress to LC or HCC.2.The gene copy number variation of PD-1 is correlated with the susceptibility of chronic hepatitis B virus,and the high PD-1 gene copy number has a significant correlation with HBV infection（LC group compared with acute HBV infection recovery period）.