Association Study Of TNFSF/TNFRSF Gene Polymorphisms With HCV Infection And Chronic

[Background]Hepatitis C virus（HCV）infection is a global public health problem that seriously endangers human health.According to the GLOBAL HEPATITIS REPORT,2017 released by the World Health Organization（WHO）,there are approximately 185 million people infected with Hepatitis C virus（HCV）worldwide,of which about 7,100 are chronically infected,and China is the country with the largest number of HCV patients worldwide.HCV infection is characterized by high occultity,high false negative rate,high chronicity,low cognitive rate and low treatment rate.At present,hepatitis C prevention still faces great challenges.The study found that the Tumor necrosis factor superfamily（TNFSF）and Tumor necrosis factor receptor superfamily（TNFRSF）plays an important role in the molecules involved in the immune regulation of viral infection cells.When HCV virus invades the body,TNFSF/TNFRSF participates in important immunoregulatory effects,which in turn affects the outcome of HCV infection.The TNFSF/TNFRSF gene polymorphism may be associated with HCV infection and chronicity.[Objective]To investigate the relationship between TNF,LTA,TNFRSF1A,TNFRSF1B and TNFRSF5 gene polymorphisms and HCV infection and chronic disease,and the possible mechanisms.[Methods]In this study,case-control studies and case-case study designs were used,and nine potential functional single nucleotide polymorphisms（SNPs）on TNF,LTA,TNFRSF1A,TNFRSF1B and TNFRSF5 genes were genotyped.By analyzing the differences between SNPs in different groups,and using the codominant model,dominant model,additive model and recessive model to analyze whether there is a correlation between the SNPs and HCV infection and chronic risk.Combined action analysis,stratification analysis,haplotype analysis and multiple stepwise regression were further carried out,and bioinformatics was used to explore the possible biological mechanism of positive sites.[Results]Individuals carrying the TNFRSF1A rs767455-T allele（additional model:adjusted OR=0.779,P=0.004）were less prone to develop HCV infection,carrying TNFRSF5 rs1535045-C（additional model:adjusted OR=1.135,P=0.032）and rs1883832-C（additional model:adjusted OR=1.127,P=0.042）were prone to develop HCV infection.The combined effect showed that with the increase of the protective alleles rs767455-C and rs1883832-C,the risk of HCV infection was decreased continuously(P=4.057×10^-4);haplotype analysis of rs1883832 and rs1535045showed that carrying CC haplotypes as comparison,carrying CT,TC,and TT haplotypes increased the susceptibility to HCV infection（P<0.05）.Through association analysis between genetic polymorphism and chronic HCV infection,it was found that patients with LTA rs1041981-A（additional model:adjusted OR=0.836,P=0.039）were less prone to chronic HCV infection and multivariate stepwise regression.Analysis showed that rs1041981 was an independent predictor of chronic HCV infection（OR=0.671,P=0.011）.Bioinformatics analysis indicated that rs767455,rs1535045,rs1883832 and rs104198 could affect the gene expression level by affecting the transcriptional regulatory activity of the corresponding gene region,and found that rs1883832 was significantly correlated with the TNFRSF5 mRNA expression level,which may affect the expression activity of the gene.[Conclusion]In Chinese Han population with high risk of HCV infection,the TNFRSF1A rs767455-T allele is a protective factor for HCV infection,the TNFRSF5rs1535045-C and rs1883832-C alleles are risk factors for HCV infection,while The LTA rs1041981-A allele is an independent protective factor for chronic HCV infection.The results of this study will provide a theoretical basis and basis for further elucidation of the mechanism of HCV infection and its chronicity,as well as the development of chronic hepatitis C prevention strategies and personalized antiviral treatment programs.