Study On The Association Of TNFSF4,TNFSF8 And Their Receptors Gene Polymorphisms With The Outcomes Of HCV Infection

[Backgrounds]Hepatitis C virus（HCV）infection has become one of the most important public health problems that caused a widespread epidemic of hepatitis C in China and even in the world.According to the estimation of World Health Organization（WHO）,about 185 million people worldwide are infected with HCV,and about 399,000people die from HCV-related diseases each year.In China,about 25 million people are infected with HCV,making the disease burden one of the highest in the world.Previous studies have established that HCV infection is a process of interaction and mutual influence among HCV virological characteristics,environmental factors,and host immunity,in which host immunity plays a leading role.Studies have shown that tumor necrosis factor superfamily（TNFSF）/tumor necrosis factor receptor superfamily（TNFRSF）alone or in combination can participate in a variety of physiological and pathological processes.Among them,TNFSF4,TNFSF8 and their receptor gene single nucleotide polymorphisms（SNPs）are linked to a variety of immune diseases,and their encoded proteins play an important role in cell survival and proliferation,inflammation and immunity.Therefore,we speculate that these immune gene mutations may affect the process of HCV infection,subsequently affecting the outcomes of HCV infection.[Objectives]To explore the relationships between TNFSF4,TNFRSF4,TNFSF8 and TNFSF8 genes SNPs and the outcomes of HCV infection and their etiological mechanisms.[Methods]This study adopts case-control study and case-case study design,and selects the high-risk groups of HCV infection（drug addicts,hemodialysis population and paid blood donation population）included in the research group since Oct 2011 as the research objects.According to scientific and strict SNPs site strategy,there are 8candidate SNPs of TNFSF4,TNFRSF4,TNFSF8 and TNFSF8 genes included in this study,and we use Taq Man-MGB technology for genotyping.According to the law of inheritance,four genetic models,co-dominant model,dominant model,recessive model,and additive model are used to analyze the internal relationship between individuals carrying different SNPs genotypes and the outcomes of HCV infection.In addition,to further explore the host（gene variation）-environmental factors and the outcomes of HCV infection and possible mechanisms of biological function through a variety of statistical analysis（such as stepwise regression analysis,joint effect analysis,hierarchical analysis and interaction analysis）and bioinformatics analysis.[Results]A total of 3690 subjects were enrolled in this study,with an average age of50.54±14.02 years old,1994（54.04%）≥50 years old,and 1870（50.68%）male.TNFSF4-rs7514229(G>T,co-dominant model:adjusted OR=6.53,95%CI=3.77-11.3,P<0.001,P_FDR=0.002;dominant model:adjusted OR=1.37,95%CI=1.13-1.66,P=0.001,P_FDR=0.007;recessive model:adjusted OR=6.40,95%CI=3.70-11.05,P<0.001,P_FDR=0.007;additive model:adjusted OR=1.52,95%CI=1.29-1.78,P<0.001,P_FDR=0.004),TNFSF4-rs3850641(A>G,co-dominant model:adjusted OR=2.18,95%CI=1.39-3.41,P=0.001,P_FDR=0.002;dominant model:adjusted OR=1.29,95%CI=1.09-1.53,P=0.002,P_FDR=0.007;recessive model:adjusted OR=2.05,95%CI=1.31-3.20,P=0.002,P_FDR=0.007;additive model:adjusted OR=1.31,95%CI=1.13-1.51,P<0.001,P_FDR=0.004),TNFSF8-rs3181366(C>T,co-dominant model:adjusted OR=1.59,95%CI=1.20-2.10,P=0.001,P_FDR=0.002;dominant model:adjusted OR=1.20,95%CI=1.03-1.40,P=0.018,P_FDR=0.032;recessive model:adjusted OR=1.50,95%CI=1.15-1.97,P=0.003,P_FDR=0.007;additive model:adjusted OR=1.21,95%CI=1.07-1.36,P=0.002,P_FDR=0.004)and TNFSF8-rs2295800(T>C,co-dominant model:adjusted OR=1.26,95%CI=1.07-1.48,P=0.005,P_FDR=0.035;dominant model:adjusted OR=1.22,95%CI=1.04-1.42,P=0.012,P_FDR=0.028)SNPs variants were significantly associated with the risk of HCV infection.Bioinformatics analysis showed that SNPs rs3181366,rs7514229,rs3850641,and rs2295800 may affect gene expression by regulating the transcriptional activity of corresponding gene regions,as well as rs3850641 and rs2295800 may affect m RNA transcription by affecting the binding of mi RNAs,leading to the changes of the structure of m RNA,or may affect promoter activation and transcription,thereby regulating disease susceptibility.[Conclusions]In Chinese high-risk population of HCV infection,TNFSF4 rs7514229-T,rs3850641-G,TNFSF8 rs3181366-T and rs2295800-C alleles increase the risk of HCV infection.This study demonstrates the progress of diseases from the perspective of population genes,strengthens the understanding of immune mechanisms,and discovers new HCV susceptible immune biomarkers,laying a solid foundation for the formulations of strategies for screening and identifying susceptible populations.