| Objective:Chronic hepatitis B(CHB)caused by chronic hepatitis B virus(HBV)infection is one of the most common infectious diseases in the clinic,and some of them can be further developed into Chronic Hepatitis B-related hepatocellular carcinoma(CHB-related HCC).CHB-related HCC is one of the common malignant tumors in China.Due to the lack of obvious symptoms in the early stage of the disease,especially hepatocellular carcinoma,and the lack of sensitive and specific biomarker for earlier diagnosis.How to early diagnosis and treatment the disease has become a key issue in the all over the world.At present,most studies recommended that susceptibility genes represented by single nucleotide polymorphisms(SNPs)and abnormal gene expression are risk factors of chronic HBV infection and CHB-related HCC.It has been reported that polymorphisms of signal transducer and activator of transcription 3(STAT3)and STAT4 might be associated with susceptibility to chronic HBV infection and risk of CHB-related HCC.Owing to limitation of sample size and inconclusive results,we conducted a meta-analysis to clarify the association.Thus,in order to provide a basis for determining the high-risk population of chronic HBV infection and CHB-related HCC and guiding early diagnosis.Methods:To search published case-control studies on the associations of STAT3 and STAT4 polymorphisms with susceptibility to chronic hepatitis B virus infection and risk of hepatocellular carcinoma,We identified relevant studies by a systematic search of Medline/PubMed,EMBASE,Web of Science and the Cochrane Library through Feb.20.2019.The search was designed using the key words"STAT3","STAT4","signal transducer and activator of transcription 3","signal transducer and activator of transcription 4","HBV","HCC","hepatocellular carcinoma","hepatitis B","polymorphism"and"SNP".The screening of the article was done independently by two reviewers.After secondary screening of all the literatures,the final eligible research literatures were determined,and the selected literatures were evaluated for quality according to the quality score table.The data extracted from the literature were input into the analysis software for data analysis to test for heterogeneity,further subgroup and sensitivity analysis,explore sources of heterogeneity,draw forest plots to show the effect value of each study,and detect publication bias.The corresponding correlation strength was measured through Odds Ratios(OR)and 95%Confidence Intervals(CIs).Finally,the data was compiled into a table to show the characteristics of the included research.The above statistical analysis is based on the Review Manager 5.3 software.To verify the authenticity of the analysis results,we performed Trial Sequential Analysis(TSA)and False Positive Report Probability(FPRP).Results:A total of 5242 cases and 2717 controls from 5 studies were included for the STAT3 polymorphism,5902 cases and 7867 controls from 9 studies for the STAT4 polymorphism.Our results suggested that rs1053004 polymorphism of STAT3 was a significant risk factor of chronic HBV infection(C vs.T:OR=1.17,95%CI:1.07-1.29,P_A=0.0007;CC+CT vs.TT:OR=1.38,95%CI:1.09-1.76,P_A=0.008;CC vs.CT+TT:OR=1.10,95%CI:0.91-1.31,P_A=0.32).Surprisingly,we did not find significant association between STAT3 rs1053004 and CHB-related HCC this time(C vs.T:OR=1.04,9 5%CI:0.93-1.15,P_A=0.52;CC+CT vs.TT:OR=1.03,9 5%CI:0.89-1.19,P_A=0.71;CC vs.CT+TT:OR=0.98,9 5%CI:0.58-1.67,P_A=0.95)?.For the STAT3 rs2293152 polymorphism,we failed to find any significant association with chronic HBV infection(G vs.C:OR=1.09,9 5%CI:0.99-1.20,P_A=0.08;GG+GC vs.CC:OR=1.12,9 5%CI:0.96-1.32,P_A=0.14;GG vs.GC+CC:OR=1.12,9 5%CI:0.95-1.32,P_A=0.18)and CHB-related HCC(G vs.C,OR=1.07,9 5%CI:0.95-1.20,P_A=0.24;GG+GC vs.CC:OR=1.06,9 5%CI:0.88-1.27,P_A=0.57;GG vs.GC+CC:OR=1.14,9 5%CI:0.94-1.38,P_A=0.17).Finally,validation with all the genetic models revealed thatrs7574865 polymorphism of STAT4 were closely associated with chronic HBV infection(G vs.T:OR=1.23,95%CI:1.15-1.32,P_A<0.00001;GG+GT vs.TT:OR=1.38,95%CI:1.18-1.61,P_A<0.0001;GG vs.GT+TT:OR=1.29,95%CI:1.19-1.41,P_A<0.00001)and CHB-related HCC(G vs.T:OR=1.18,95%CI:1.07-1.31,P_A=0.001;GG+GT vs.TT:OR=1.26,95%CI:1.04-1.53,P_A=0.02;GG vs.GT+TT:OR=1.20,95%CI:1.06-1.37,P_A=0.005).Meanwhile,the authenticity of the above meta-analysis results was confirmed by trial sequential analysis and False-positive report probability analysis.Conclusion:The meta-analysis showed that STAT3 rs1053004 polymorphism may be the risk for developing chronic HBV infection but not associated with CHB-related HCC.Neither chronic HBV infection nor CHB-related HCC could show significant connection with STAT3 rs2293152 polymorphisms.The present study also indicates that STAT4 rs7574865 polymorphism increased the risk of chronic HBV infection and CHB-related HCC.However,the correlation between genetic polymorphisms and chronic HBV infection and CHB-related HCC needs to be further studied.This conclusion may be an important basis for identifying susceptible populations,early diagnosis,disease stage and prognosis analysis. |
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