Genetic Mutations in TNFSF11 Were Associated With the Chronicity of Hepatitis C Among Chinese Han Population

Background: Recently, several studies have reported that the host immune response can be related to the RANKL/RANK/OPG signaling pathway. However, the associations of TNFSF11, TNFRSF11A, and TNFRSF11B gene polymorphisms in the RANKL/RANK/OPG pathway with hepatitis C virus (HCV) infection outcomes remain unclear.Methods: In this case-control study, 768 persistent HCV infection and 503 spontaneous HCV clearance cases, and 1,259 control subjects were included. The Taman-MGB probe method was utilized to detect TNFSF11 rs9525641, TNFRSF11A rs8686340, and TNFRSF11B rs2073618 genotypes. The distribution of three single nucleotide polymorphisms (SNPs) genotypes was analyzed using stata14.0.Results: SNPs rs9525641, rs8086340, and rs2073618 genotype frequencies followed the Hardy-Weinberg natural population equilibrium (p = 0.637, 0.250, and 0.113, respectively). Also, rs9525641 was significantly associated with HCV chronicity risk in recessive (OR = 1.203, 95% CI: 1.018–1.420, p = 0.030) and additive models (OR = 1.545, 95% CI: 1.150–2.075, p = 0.004). The stratified analysis showed that rs9525641 variant genotypes were associated with HCV chronicity among people older than 50 years (OR =1.562, 95% CI: 1.079–2.262, p = 0.018), females (OR = 1.667, 95% CI: 1.145–2.429, p = 0.008), ALT <40 U/L (OR = 1.532, 95% CI: 1.074–2.286, p = 0.018), and AST < 40 U/L (OR = 1.552, 95% CI: 1.095–2.201, p = 0.014).Conclusion:TNFRSF11 rs9525641 was significantly associated with HCV chronicity in the Chinese population.

Paraoxonase 1 gene (PON1) variants concerning hepatitis C virus (HCV) spontaneous clearance in hemodialysis individuals: a case–control study

Background To explore associations between PON1 rs854560, rs662, 705,379, HCV clearance, and interactions between tested PON1 single nucleotide variants (SNVs) and interferon-λ4 gene (IFNL4) rs368234815 variant in hemodialyzed individuals. Methods The study included 83 HD individuals who spontaneously resolved HCV infection (all had known IFNL4 rs368234815 variant) and 104 individuals with persistently positive blood tests for HCV RNA (102 were IFNL4 rs368234815 variant successfully genotyped). We genotyped PON1 by high-resolution melt analysis (rs662) or predesigned TaqMan SNV Genotyping Assay (rs854560, rs705379). We used a logistic regression model to assess the association between genetic data and HCV outcome while adjusting for clinical confounding variables. Epistatic interactions between tested PON1 SNVs and IFNL4 rs368234815 were analyzed by the multifactor dimensionality reduction method. Results In the recessive inheritance model, PON1 rs662 GG (OR 9.94, 95% CI 1.20–82.7, P = 0.022) and rs854560 TT (OR 4.31, 95% CI 1.62–11.5, P = 0.003) genotypes were associated with a higher probability for HCV clearance. The haplotype composed of rs662A_rs854560A_rs705379 was not associated with spontaneous HCV clearance. The IFNL4 rs368234815 TT/TT variant was equally distributed among individuals bearing different PON1 SNVs. The epistatic gene–gene analysis did not reveal the interaction between tested PON1 SNVs and IFNL4 rs368234815 (P = 0.094). Regression model, including the PON1 rs662 GG genotype, the PON1 rs854560 genotype, the IFNL4 rs368234815 TT/TT genotype, age at RRT onset, RRT duration, and chronic glomerulonephritis as possible explanatory variables for spontaneous HCV clearance, showed that significant predictors of spontaneous HCV clearance were the IFNL4 rs368234815 TT/TT genotype (OR 2.607, 95% CI 1.298—5.235, P = 0.007), PON1 rs854560 TT (OR 6.208, 1.962–19.644, P = 0.002), PON1 rs662 GG (OR 10.762, 1.222–94.796, P = 0.032), and RRT duration (OR 0.930, 95% CI 0.879–0.984, P = 0.011). Conclusion In HD individuals, PON1 rs662 GG and rs854560 TT are associated with a higher frequency of spontaneous HCV clearance.

Genetic Variants in TNFSF4 and TNFSF8 Are Associated With the Risk of HCV Infection Among Chinese High-Risk Population

BackgroundThe tumor necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) play important roles in the immune responses to infections. The aim of this study was to determine the impact of single nucleotide polymorphisms (SNPs) of several TNFSF/TNFRSF genes on the risk of hepatitis C virus (HCV) infection in the Chinese high-risk population.MethodsThe TNFSF4-rs1234313, TNFSF4-rs7514229, TNFSF8-rs3181366, TNFSF8-rs2295800, TNFRSF8-rs2298209, and TNFRSF8-rs2230625 SNPs were genotyped in 2309 uninfected controls, 597 subjects with spontaneous HCV clearance and 784 patients with persistent HCV infection using the TaqMan-MGB assay. The putative functions of the positive SNPs were determined using online bioinformatics tools.ResultsAfter adjusting for gender, age, high-risk population, alanine transaminase (ALT), aspartate aminotransferase (AST), IL28B-rs12979860 and rs8099917 genotypes, the non-conditional logistic regression showed that rs7514229-T, rs3181366-T, and rs2295800-C were associated with an increased risk of HCV infection (all PFDR < 0.05). Combined analysis of rs7514229-T and rs3181366-T risk alleles showed that the subjects carrying 2–4 risk alleles were more susceptible to HCV infection compared with those lacking any risk allele (all P < 0.001). Furthermore, the risk of HCV infection increased with the number of risk alleles (Ptrend < 0.001). In silico analysis showed that rs7514229, rs3181366, and rs2295800 polymorphisms may affect the transcription of mRNA by regulating miRNA binding, TF binding, and promoter activation, respectively, which may have biological consequences.ConclusionTNFSF4-rs7514229, TNFSF8-rs3181366, and TNFSF8-rs2295800 are associated with increased risk of HCV infection in the Chinese high-risk population.

Polymorphism rs368234815 of interferon lambda 4 gene and spontaneous clearance of hepatitis C virus in haemodialysis patients: a case-control study

Background In non-uremic subjects, IFNL4 rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms. Methods Among 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software. Results The probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38–5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45–5.43, 0.002 for rs12980275 and 2.44, 1.27–4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69–24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rank P = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1. Conclusions In haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for other IFNL3/IFNL4 polymorphisms only in the additive mode of inheritance. However, identifying the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that we observe in the case of the variant homozygosity of other tested IFNL3/IFNL4 polymorphisms. Removal of PLAGL1 TFBS in subjects harbouring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.

Polymorphism rs368234815 Of Interferon Lambda 4 Gene And Spontaneous Clearance Of Hepatitis C Virus In Haemodialysis Patients: A Case-Control Study

Background: In non-uremic subjects, IFNL4 rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms.Methods: Among 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software. Results: The probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38–5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45–5.43, 0.002 for rs12980275 and 2.44, 1.27–4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69–24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rank P = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1. Conclusions: In haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for other IFNL3/IFNL4 polymorphisms only in the additive mode of inheritance. However, identifying the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that we observe in the case of the variant homozygosity of other tested IFNL3/IFNL4 polymorphisms. Removal of PLAGL1 TFBS in subjects harbouring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.

Polymorphism rs368234815 of Interferon Lambda 4 Gene and Spontaneous Clearance of Hepatitis C Virus in Haemodialysis Patients: A Case Control Study

BackgroundIn non-uremic subjects, IFNL4 rs368234815 predicts the HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in haemodialysis subjects. An association of rs368234815 with survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms were also evaluated. MethodsAmong 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. The Kaplan-Meier method with the log-rank test was used for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software. Results: The probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38–5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45–5.43, 0.002 for rs12980275 and 2.44, 1.27–4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69–24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rank P = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1. ConclusionsIn haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for other IFNL3/IFNL4 polymorphisms only in the additive mode of inheritance. However, an identification of the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that it is observed in the case of the variant homozygosity of other tested IFNL3/IFNL4 polymorphisms. Removal of PLAGL1 TFBS in subjects harboring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.

Spontaneous Clearance of Chronic HCV: The Key Ending Left in the Dark

BACKGROUND: Hepatitis C is the second leading cause of liver cirrhosis and hepatocellular carcinoma. Although the discovery of direct-acting agents made the disease curable, HCV elimination can be achieved solely by the host’s immunologic arsenal. CASE REPORT: We report the case of a 29-year-old woman with chronic hepatitis C infection - elevated transaminases, positive serology. HCV was detectable on two occasions, and histology showed mild disease - A1F1. Upon follow up and without any treatment, the patient achieved spontaneous clearance confirmed by two consecutive undetectable HCV RNA tests. Spontaneous HCV clearance rarely occurs – 0.5% per person-year. This is sometimes accompanied by special circumstances like additional disease or medical interventions. Host factors like gender and interleukin-28B polymorphisms have been known to contribute to clearance. Viral factors like HCV RNA levels are also a factor. The characteristics of host-viral interplay – age of acquisition and fibrosis stage – cannot be overlooked. CONCLUSION: All of the abovementioned factors contribute to the complex immunological interaction between virus and host and the result, although rarely can be spontaneous clearance.

Spontaneous Clearance of Hepatitis C Virus in a Patient Co- Infected with Hepatitis C Virus and Human Immunodeciency Virus: a Case Report

The effect of highly active antiretroviral therapy (HAART) on hepatitis C virus (HCV) infection remains unclear. Spontaneous HCV clearance with initiation of HAART in non-cirrhotic HCV patients co-infected with human immunodeficiency virus (HIV) has been reported. We describe an HIV/HCV patient with decompensated cirrhosis, who had spontaneous HCV clearance after an episode of elevated liver enzymes and a change in HAART regimen. His HCV RNA level remained undetectable for six months by quantitative and qualitative polymerase chain reaction (PCR) tests. The disappearance of HCV RNA may be due to a combination of host immune recovery, genetic polymorphism and direct effect of HAART against HCV.