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The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (p trend  = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection., (© 2024 Wiley Periodicals LLC.)

Background: The current study uniquely focuses on the global incidence and temporal trends of acute hepatitis C (AHC) and hepatitis C virus (HCV)-related cirrhosis among women of reproductive age (15-49 years) from 1990-2019. The risk of vertical transmission and adverse perinatal outcomes associated with HCV infection underscores the importance of prioritising these women in HCV prevention efforts., Methods: Leveraging the Global Burden of Disease 2019 data, we calculated age-standardised incidence rates (ASIR) and assessed temporal trends via the average annual percent change from joinpoint regression. The age-period-cohort model was employed to understand further the effects of age, period, and birth cohort., Results: Over the 30 years, global incidences of AHC and HCV-related cirrhosis in reproductive-age women increased by 46.45 and 72.74%, respectively. The ASIR of AHC was highest in low sociodemographic index regions but showed a declining trend. Conversely, the ASIR of HCV-related cirrhosis displayed unfavourable trends in low, low-middle, and high sociodemographic index regions. Special attention is necessary for sub-Saharan Africa, high-income North America, Eastern Europe, and Central Asia due to their high incidence rates or increasing trends of AHC and HCV-related cirrhosis. Notably, the age-period-cohort model suggests a recent resurgence in AHC and HCV-related cirrhosis risk., Conclusions: The current study is the first to thoroughly evaluate the trends of AHC and HCV-related cirrhosis among reproductive-age women, shedding light on previously unexplored aspects of HCV epidemiology. Our findings identify critical areas where health care systems must adapt to the changing dynamics of HCV infection. The detailed stratification by region and nation further enables the development of localised prevention and treatment strategies., Competing Interests: Disclosure of interest: The authors have completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background: Most existing predictive models of hepatocellular carcinoma (HCC) risk after sustained virologic response (SVR) are built on data collected at baseline and therefore have limited accuracy. The current study aimed to construct an accurate predictive model incorporating longitudinal data using a novel modeling strategy. The predictive performance of the longitudinal model was also compared with a baseline model., Methods: A total of 400 patients with HCV-related cirrhosis who achieved SVR with direct-acting antivirals (DAA) were enrolled in the study. Patients were randomly divided into a training set (70%) and a validation set (30%). Informative features were extracted from the longitudinal variables and then put into the random survival forest (RSF) to develop the longitudinal model. A baseline model including the same variables was built for comparison., Results: During a median follow-up time of approximately 5 years, 25 patients (8.9%) in the training set and 11 patients (9.2%) in the validation set developed HCC. The areas under the receiver-operating characteristics curves (AUROC) for the longitudinal model were 0.9507 (0.8838-0.9997), 0.8767 (0.6972,0.9918), and 0.8307 (0.6941,0.9993) for 1-, 2- and 3-year risk prediction, respectively. The brier scores of the longitudinal model were also relatively low for the 1-, 2- and 3-year risk prediction (0.0283, 0.0561, and 0.0501, respectively). In contrast, the baseline model only achieved mediocre AUROCs of around 0.6 (0.6113, 0.6213, and 0.6480, respectively)., Conclusions: Our longitudinal model yielded accurate predictions of HCC risk in patients with HCV-relate cirrhosis, outperforming the baseline model. Our model can provide patients with valuable prognosis information and guide the intensity of surveillance in clinical practice., (© 2023. The Author(s).)

Object: The hepatitis C virus (HCV) is prevalent across China, with a distinctive genotypic distribution that varies by geographical region and mode of transmission. Yunnan is one such geographical region wherein the local population continues to experience a high level of HCV infection, severely straining public health resources. This high prevalence is likely due to the increased incidence of intravenous drug use in that region, as Yunnan is a major point of entry for illegal heroin into China., Methods: We investigated 510 individuals with chronic HCV infections in Yunnan Province from 2008 through 2018. Using reverse transcription PCR and Sanger sequencing to amplify and sequence samples. Bayesian analyses was performed to estimate the common ancestors and Bayesian skyline plot to estimate the effective viral population size. Molecular network was conducted to explore the characteristics of HCV transmission., Results: We successfully amplified and sequenced a total of 503 viral samples and genotyped each as either 3b (37.6%), 3a (21.9%), 1b (19.3%), 2a (10.5%), HCV-6 (10.1%), or 1a (0.6%). Over this 11-year period, we observed that the proportion of 3a and 3b subtypes markedly increased and, concomitantly, that the proportion of 1b and 2a subtypes decreased. We also performed Bayesian analyses to estimate the common ancestors of the four major subtypes, 1b, 2a, 3a, and 3b. Finally, we determined that our Bayesian skyline plot and transmission network data correlated well with the changes we observed in the proportions of HCV subtypes over time., Conclusions: Taken together, our results indicate that the prevalence of HCV 3a and 3b subtypes is rapidly increasing in Yunnan, thus demonstrating a steadily growing public health requirement to implement more stringent preventative and therapeutic measures to curb the spread of the virus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jia, Zou, Yue, Liu, Yue, Liu, Liu, Huang, Feng and Xia.)

Killer-cell immunoglobulin-like receptors 2DL4 (KIR2DL4) and the human leukocyte antigen class I-G (HLA-G) display vital parts in immune responses against hepatitis C virus (HCV) infection. We select four potentially functional single nucleotide polymorphisms (SNPs) of KIR/HLA to explore the associations between KIR2DL4/HLA-G genetic variants and HCV infection results. In the present case-control study, a total of 2225 HCV-infected high-risk subjects, including 1778 paid blood donors (PBD) and 447 drug users were consecutively recruited before treatment from 2011 to 2018. KIR2DL4-rs660773, KIR2DL4-rs660437, HLA-G-rs9380142, and HLA-G-rs1707 SNPs were sorted as genotypes in the subdivided groups, involving 1095 uninfected controls subjects, 432 spontaneous HCV clearance subjects and 698 HCV persistent infection subjects. After genotyping experiments using the TaqMan-MGB assay, modified logistic regression was used to calculate the correlation among the SNPs and HCV infection. The SNPs were functionally annotated using bioinformatics analysis. Following adjusting by age, sex, alanine aminotransferase, aspartate aminotransferase, IFNL3-rs12979860, IFNL3-rs8099917, and the infection route, the logistic regression analysis discovered that KIR2DL4-rs660773 and HLA-G-rs9380142 were correlated with vulnerability to HCV infection (all p < 0.05). In a locus-dosage way, compared with subjects carrying the rs9380142-AA or rs660773-AA genotypes, subjects with rs9380142-AG or rs660773-AG/GG (all p < 0.05) were more vulnerable to HCV infection; the overall impact of their risk genotypes (rs9380142-AGrs660773-AG/GG) was correlated with an elevated incidence of HCV infection (p trend  < 0.001). In the Haplotype analysis, patients with haplotype AG were more likely to contract HCV compared to those with the highest common AA haplotype (p = 0.002) were higher in susceptibility to infect HCV. The SNPinfo web server estimated that rs660773 is a transcription factor binding site, whereas rs9380142 is a potential microRNA-binding site. In two Chinese high-risk population (PBD and drug uesrs), KIR2DL4 rs660773-G and HLA-G rs9380142-G alleles polymorphisms are related to HCV susceptibility. KIR2DL4/HLA-G pathway genes might affect the innate immune responses by regulating KIR2DL4/HLA-G transcription and translation play a potential role in HCV infection., (© 2023 Wiley Periodicals LLC.)

Introduction: Viral hepatitis is a global public health problem, and China still faces great challenges to achieve the WHO goal of eliminating hepatitis., Methods: This study focused on hepatitis B and C, aiming to explore the long-term spatiotemporal heterogeneity of hepatitis B and C incidence in China from 2010 to 2018 and quantify the impact of socioeconomic factors on their risk through Bayesian spatiotemporal hierarchical model., Results: The results showed that the risk of hepatitis B and C had significant spatial and temporal heterogeneity. The risk of hepatitis B showed a slow downward trend, and the high-risk provinces were mainly distributed in the southeast and northwest regions, while the risk of hepatitis C had a clear growth trend, and the high-risk provinces were mainly distributed in the northern region. In addition, for hepatitis B, illiteracy and hepatitis C prevalence were the main contributing factors, while GDP per capita, illiteracy rate and hepatitis B prevalence were the main contributing factors to hepatitis C., Disussion: This study analyzed the spatial and temporal heterogeneity of hepatitis B and C and their contributing factors, which can serve as a basis for monitoring efforts. Meanwhile, the data provided by this study will contribute to the effective allocation of resources to eliminate viral hepatitis and the design of interventions at the provincial level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qian, Yue, Huang, Ai, Zhu, Wang, Luo, Yue, Wu, Zhang, Wang and Tan.)

Hepatitis C remains a major public health problem in the world. The host immune system plays a key role in viral clearance. This study aimed to investigate the connection between retinoic acid-inducible gene I-like (RIG-I-like) receptor gene polymorphism and hepatitis C chronicity in the Chinese Han population. The current study genotyped three SNPs (IFIH1 rs10930046 and DHX58 rs2074158, rs2074160) to assess their association with the chronicity of hepatitis C virus (HCV) infection among 1,590 participants (590 spontaneous HCV clearance cases and 1,000 persistent infection patients). Our research shows that DHX58 rs2074158-G allele (dominant model: adjusted OR = 1.53, 95% CI [1.20-1.95], P  = 0.001; additive model: adjusted OR = 1.50, 95% CI [1.27-1.78], P  < 0.001) and IFIH1 rs10930046-C allele (additive model: adjusted OR = 1.26, 95% CI [1.07-1.49], P  = 0.005) were associated with chronic hepatitis C (CHC). And the risk of CHC increased in people carrying more unfavorable genotypes (rs2074158-AG/GG or rs10930046-CC), with the chronic rates for genotypes number from zero to two in 60.69%, 57.33%, and 85.93%, respectively (adjusted OR = 3.64, 95% CI [2.18-6.08]; P  < 0.001). Genetic polymorphism of IFIH1 and DHX58 may be related to CHC in the Chinese Han population. Furthermore, the risk of CHC increases as the number of unfavorable genotypes carried by the HCV-infected person increases. IFIH1 rs10930046, DHX58 rs2074158, age, ALT, and AST levels were all independent predictors of CHC., Competing Interests: The authors declare there are no competing interests., (©2023 Huang et al.)

Introduction: Hepatitis C virus (HCV) infection was the primary reason causing critical hepatic Q7 diseases. Although direct-acting antiviral agents (DAA) were widely used in clinics, anti-drug mutation, the outcome of patients with different viral subtypes, and recurrence suggested that HCV pathogenic mechanism should be studied further. HCV infection, replication, and outcome were influenced by the IFNL4 and itsdownstream genes (MxA and MxB). However, whether genetic polymorphisms of these genes played necessary roles required verification in the Yunnan population., Methods and Results: After analyzing the genotypes and allele frequencies of seven single nucleotide polymorphisms (SNP), we found the association between the genotype and allele frequencies of rs11322783 in the IFNL4 gene and HCV infection in Yunnan population. Furthermore, the genetic polymorphisms of the MxA and MxB genescould influence liver function of HCV patients. The indirect bilirubin (IBIL) and albumin (ALB) levels showed significant differences among HCV patients, who carried various genotypes. The IBIL levels were associated with genotypes of rs17000900 (P= 0.025) and rs2071430 (P= 0.037) in the MxA gene, and ALB levels were associated with genotypes of rs2838029 (P= 0.010) in the MxB gene. Similarly, the genotypes of SNPs also showed significant difference in patients infected with subtype 3a (P=0.035) and 2a (P=0.034). However, no association was identified between expression level and SNPs of the MxA and MxB genes. Furthermore, HCV subtype 3b was found to be the predominantly epidemic strain in Yunnan Province., Conclusion: In conclusion, the association between biochemical indices/HCV subtypes and SNPs in the MxA and MxB genes was identified in Yunnan HCV population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Liu, Geng, Liu, Huang, Yue, Xia and Zhang.)

The De Ritis ratio has good diagnostic accuracy in patients with chronic viral liver disease. However, its prognostic utility has remained controversial. This study was to identify different trajectories of De Ritis ratio in those hepatitis C patients cured and analyze the relationship between trajectory groups and risk of hepatocellular carcinoma (HCC) with liver-related mortality by the retrospective cohort study. This retrospective longitudinal cohort included 1241 patients with hepatitis C who underwent antiviral therapy since follow-up in 2012. De Ritis ratio trajectories were identified by the latent class growth mixed model. Patients were grouped into subgroups by De Ritis ratio according to longitudinal trajectories. The endpoints were HCC and liver-related mortality. Three distinct trajectory groups were characterized for serum De Ritis ratio: low-stable, middle-stable and high-rising. Fifty-one HCC and 11 liver-related mortality were recorded and tracked. Compared to the low-stable group, the adjusted hazard ratios (HRs) and 95% confidence interval (CI) associated with HCC and liver-related mortality were 2.02 (1.12 to 3.63), 9.36 (3.61 to 24.29), for the middle-stable, and high-rising group, respectively. Notably, the high-rising trajectory group still had prognostic significance after adjusting for preoperative levels. Likewise, for the high-rising trajectory group of sustained virological response, the HRs (95% CI) were 2.85 (1.03 to 10.75) for HCC and liver-related mortality, and in patients with cirrhosis, the HRs (95% CI) were 3.44 (1.64 to 7.19) and 4.35 (1.27 to 14.84) in the middle-stable trajectory group and the high-rising trajectory group, respectively. The dynamic measurements of De Ritis ratio are recommended to monitor the prognosis of Hepatitis C patients., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Aims: Sofosbuvir-velpatasvir-voxilaprevir is a pangenotypic regimen for chronic HCV infection. In the USA and Europe, sofosbuvir-velpatasvir-voxilaprevir once daily for 12 weeks is indicated for adults who previously received an HCV NS5A inhibitor. In Europe, sofosbuvir-velpatasvir-voxilaprevir is also indicated in the absence of prior HCV direct-acting antiviral (DAA) therapy as an 8-week or 12-week regimen. In an open-label study, we evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years with chronic HCV of any genotype., Methods: In this Phase 2, multicenter study, sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg daily was administered to adolescents for 8 weeks if DAA-naïve or for 12 weeks for cirrhosis or prior DAA failure. The key efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Intensive pharmacokinetic sampling was done in 14 patients at week 2 or 4, and samples for population pharmacokinetics were collected in all patients., Results: All patients (n = 21) were naïve to HCV DAAs, and none had cirrhosis. HCV genotype 3a infection was most common, occurring in 43% of patients. Overall, 100% of patients (21 of 21) reached SVR12. The most common adverse events were abdominal pain and headache (24% each) and nausea (19%); no adverse events led to discontinuation. The only serious adverse event, hypotension, was considered related to study drug and resolved the same day without interruption of treatment. Sofosbuvir-velpatasvir-voxilaprevir exposures were similar to those observed in adults., Conclusions: The pangenotypic regimen of sofosbuvir-velpatasvir-voxilaprevir is highly efficacious and well-tolerated in treating chronic HCV infection in adolescents., (© 2022 American Association for the Study of Liver Diseases.)

Background & Aims: The risk for hepatitis C virus (HCV) recurrence persists after HCV eradication with direct-acting antivirals (DAAs), particularly in patients with ongoing high-risk behaviours. Our aim was to assess the risk of HCV recurrence (late relapse and/or reinfection) post-sustained virological response (SVR)., Methods: We searched the literature for studies reporting HCV recurrence rates post-SVR in PubMed, Web of Science and the Cochrane Library. Identified publications were divided into groups based on patient risk for HCV reinfection: low-risk HCV mono-infection, high-risk HCV mono-infection and a human immunodeficiency virus (HIV)/HCV coinfection. The HCV recurrence rate for each study was calculated by using events divided by the person-years of follow-up (PYFU). HCV recurrence was defined as confirmed, detectable HCV RNA post-SVR., Results: In the 16 studies of low-risk patients, the pooled recurrence rate was 0.89/1000 PYFU (95% confidence interval [CI], 0.16-2.03). For the 19 studies of high-risk patients, the pooled recurrence rate was 29.37/1000 PYFU (95% CI, 15.54-46.91). For the eight studies of HIV/HCV-coinfected patients, the pooled recurrence rate was 23.25/1000 PYFU (95% CI, 4.24-53.39). The higher pooled estimates of recurrence in the high-risk and HIV/HCV-coinfected populations were predominantly driven by an increase in reinfection rather than late relapse., Conclusions: The HCV recurrence risk after achieving SVR with all-oral DAAs therapy is low, and the risk of HCV recurrence in high-risk and HIV/HCV-coinfected populations was driven by an increase in reinfection rather than late relapse., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: KIR/HLA-C signaling pathway influences the innate immune response which is the first defense to hepatitis C virus (HCV) infection. The aim of this study was to determine the association between the genetic polymorphisms of KIR/HLA-C genes and the outcomes of HCV infection in a high-risk Chinese population., Methods: In this case-control study, four single nucleotide polymorphisms (SNPs) of KIR/HLA-C genes ( KIR2DS4 / KIR2DS1 / KIR2DL1 rs35440472, HLA-C rs2308557, HLA-C rs1130838, and HLA-C rs2524094) were genotyped by TaqMan assay among drug users and hemodialysis (HD) patients including 1,378 uninfected control cases, 307 subjects with spontaneous viral clearance, and 217 patients with persistent HCV infection. Bioinformatics analysis was used to functionally annotate the SNPs., Results: After logistic regression analysis, the rs35440472-A and rs1130838-A alleles were found to be associated with a significantly elevated risk of HCV infection (OR = 1.562, 95% CI: 1.229-1.987, P < 0.001; OR = 2.134, 95% CI: 1.180-3.858, P = 0.012, respectively), which remained significant after Bonferroni correction (0.05/4). The combined effect of their risk alleles and risk genotypes (rs35440472-AA and rs1130838-AA) were linked to the increased risk of HCV infection in a locus-dosage manner (all P trend < 0.001). Based on the SNPinfo web server, rs35440472 was predicted to be a transcription factor binding site (TFBS) while rs1130838 was predicted to have a splicing (ESE or ESS) function., Conclusion: KIR2DS4 / KIR2DS1 / KIR2DL1 rs35440472-A and HLA-C rs1130838-A variants are associated with increased susceptibility to HCV infection in a high-risk Chinese population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shen, Ge, Dong, Wang, Shao, Cai, Huang, Fan, Li, Zhang and Yue.)

Hepatitis C virus (HCV) infections are a serious global-scaled public health problem. Tumor necrosis factor (TNF)/lymphotoxin alpha (LTA) has been found to play a crucial role in relation to the outcomes of HCV infection after it binds to TNF receptor superfamily member 1A (TNFRSF1A). Thus, we investigated whether or not the TNF/LTA gene cluster and TNFRSF1A gene polymorphisms were associated with the outcomes of HCV infection. 1103 control participants without HCV infection, 497 patients with spontaneous clearance of HCV infection, and 713 patients with persistent HCV infection were enrolled. Rs2229094, rs1041981, rs1799964, and rs767455 were genotyped using the ABI TaqMan allelic discrimination assay. After adjusting for age, gender, and after determining a high-risk population, we used logistic regression analyses for which results indicated that the rs767455-C allele was associated with a reduced risk of HCV infection compared to respective results for the wild-type T allele (dominant model: adjusted OR = 0.74, 95% CI = 0.60-0.92, P = .006; additive model: adjusted OR = 0.76, 95% CI = 0.62-0.91, P = .004). Results also indicated that the rs1041981-A allele was associated with a decreased risk of persistent HCV infection compared to respective results for the wild-type C allele (additive model: adjusted OR = 0.81, 95% CI = 0.68-0.96, P = .017). Genetic polymorphisms in the LTA and TNFRSF1A genes were found to have been potentially important in relation to the susceptibility and chronicity of HCV infection among Chinese Han population.

Background: The Fas cell surface death receptor (FAS) and Fas ligand (FASL) can participate in the apoptosis of immune cells and target cells infected with a virus through the FAS-FASL signalling pathway. The decoy receptor 3 (DCR3) can competitively inhibit the binding of FAS to FASL. Our aim is to investigate the effect of single nucleotide polymorphisms (SNPs) in FAS, FASL and DCR3 on hepatitis C virus (HCV) infection., Methods: Four SNPs (rs763110 in FASL , rs1324551 and rs2234767 in FAS and rs2257440 in DCR3 ) were genotyped in 1495 controls free of HCV, 522 individuals with spontaneous HCV clearance and 732 patients with hepatitis C virus infection. The RegulomeDB database and RNAfold web servers were used to explore potential biological functions of SNPs., Results: FASL rs763110 was associated with susceptibility to HCV infection, and not to CHC. The odds ratio (95% confidence interval) of HCV infection in high-risk populations carrying FASL rs763110-TT was 1.82 (1.36-2.51, P < 0.001) compared to that of CC genotypes and 1.93 (1.43-2.60, P < 0.001) higher than that of CC + CT genotypes. Based on computer simulation, FASL rs763110-T may affect the transcription of mRNA by affecting the binding of a transcription factor, leading to structural changes in mRNA., Conclusion: The genetic variant in FASL is linked with HCV infection, but not to spontaneous HCV clearance.

Objective: To investigate the tumor necrosis factor receptor superfamily 1B gene (TNFRSF1B) polymorphism in relation to the outcomes of hepatitis C virus (HCV) infection. Methods: One thousand six hundred and forty-five cases without HCV infection, 545 cases with HCV clearance, and 783 cases with chronic HCV infection were enrolled. TaqMan probe method was used to investigate genotype rs1061622 (T > G) and rs1061624 (G > A). Two single nucleotide polymorphisms (SNPs) sites were genotyped and haplotypes were constructed to evaluate their relation with the outcome of HCV infection. Results: Logistic regression analysis showed that there was no relation to the two SNPs with HCV infection susceptibility and chronicity ( P > 0.05). Haplotype analysis showed that carrier TA had an increased susceptibility to HCV infection [adjusted odds ratio ( OR ) = 1.15, 95% confidence interval ( CI ): 1.01 to 1.30, P = 0.038)]. Carrier TA and GG haplotypes were conducive to chronic HCV infection (adjusted OR = 1.28, 95% CI : 1.08 to 1.53, P = 0.006; OR = 1.31, 95% CI : 1.03 to 1.66, P = 0.026). Conclusion: The combinational effects of rs1061622 and rs1061624 in TNFRSF1B gene may increase the risk of HCV chronicity and infection.

Background: CD40, encoded by TNFRSF5, participates in the survival of B cells, process of antigen presentation and generation of CD8+ T cell memory. It also has an important effect on HCV antiviral immune response. This study aims to investigate whether TNFRSF5 gene polymorphisms are associated with HCV infection outcomes among Chinese population., Methods: Three single nucleotide polymorphism (SNPs) (rs1535045, rs1883832, rs4810485) on TNFRSF5 were genotyped by TaqMan assay among Chinese population, including 1513 uninfected subjects, 496 spontaneous viral clearance subjects and 768 persistent HCV-infected subjects. Logistic analysis was used to compare these SNPs among different groups in this cross-sectional study. Functional annotations of the identified SNPs were further evaluated by bioinformatics analysis., Results: After adjusted by age, gender and routes of infection, the results of logistic analysis indicated that individuals carrying rs1535045 T allele had a higher risk to infect HCV compared with C allele (in recessive model, adjusted OR = 1.368, 95%CI = 1.070-1.749, P = 0.012). Subjects carried rs1535045 TT genotype were more likely to infect HCV than wild CC genotype (adjusted OR = 1.397, 95%CI = 1.078-1.809, P = 0.011). For rs1883832, T allele was significantly associated with an increased risk of HCV infection (in recessive model, adjusted OR = 1.337, 95%CI = 1.069-1.673, P = 0.011). Subjects with TT genotype had more possibility to infect HCV (adjusted OR = 1.351, 95%CI = 1.060-1.702, P = 0.015). In the stratified analysis, rs1535045 and rs1883832 were remained in various subgroups and the heterogeneity test showed no pronounced heterogeneity in any pairwise comparison (all P > 0.05). In addition, the results of the cumulative effects showed a tendency of that the more risk alleles (rs1535045 T and rs1883832 T) subjects carried, the more possibility of HCV infection exhibited (P<0.001). In haplotype analyses, compared with the CC haplotype, CT, TC and TT was correlated with an increased risk to infect HCV (P = 0.029, P = 0.047 and P<0.001, respectively)., Conclusions: In conclusion, CD40 polymorphisms were significantly associated with the susceptibility to HCV among Chinese populations.

Host genetic polymorphism is one of major unalterable major factors for HCV infection. NF-κB proteins play multiple roles in immune response and involve in HCV infection and progression. This study was conducted to explore the relationship between single nucleotide polymorphisms (SNPs) in NF-κB pathway and the susceptibility as well as resolution of HCV infection. A total of 1642 Chinese subjects were enrolled in the study, including 963 uninfected control cases, 231 cases with spontaneous viral clearance and 448 cases with persistent HCV infection, and four SNPs (Rel rs842647, NF-κB2 rs12769316, RelA rs7101916, RelB rs28372683) were genotyped by TaqMan assay among them. Potentially functional polymorphisms were analyzed using online bioinformatics tools. The logistic analyses results indicated that RelA rs7101916 T allele (P Bonferroni  = 0.016) and RelB rs28372683 A allele (P Bonferroni  = 4.8e-5) were associated with an decreased risk of the susceptibility to HCV infection among Chinese Han population, which were consistent with the results of cumulative effects and haplotype analysis. The silico analysis of SNPs function suggested that the genetic variation of rs7101916 and rs28372683 could influence gene transcriptional regulation and expression, subsequently affecting NF-κB pathway activation and the susceptibility to HCV infection. This study firstly reported that the carriage of RelA rs7101916 T or RelB rs28372683 A was the potential protective factor against HCV infection among the Chinese population.

Vitamin D binding protein (VDBP) plays an important role in the immune modulation and pathogenesis of hepatitis C viral (HCV) infection by influencing serum vitamin D levels. The present study aims to evaluate the association of VDBP genetic polymorphisms with susceptibility to and chronicity of HCV infection in a high-risk Chinese population. Seven genetic variants in the VDBP gene were genotyped in a case-control study of 886 patients with HCV persistent infection, 539 subjects with spontaneous clearance, and 1081 uninfected controls. Logistic regression analysis was used to assess the effects of these variants on HCV infection outcomes. The results showed that two variants rs7041-G and rs3733359-T alleles were significantly associated with increased susceptibility of HCV infection, and the combined effect of the two unfavorable alleles was related to an elevated risk of HCV infection in a locus-dosage manner (P trend  = 8.16 × 10 -4 ). Interaction analysis manifested that rs7041-GT/GG and rs3733359-CT/TT jointly increased risk of HCV infection. Moreover, haplotype analysis suggested that compared with the most frequent TC haplotype, the haplotype carrying GT indicated a risk effect of HCV infection [odds ratio (OR) = 1.464]. However, no significant associations were observed for the other five variants. These findings implied that VDBP rs7041-G and rs3733359-T variants may contribute to increased susceptibility to HCV infection in a high-risk Chinese population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: To investigate whether nuclear factor-kappa B1 (NFKB1) gene polymorphisms are associated with the outcomes of hepatitis C virus (HCV) infection in a Chinese high-risk population., Methods: In this case-control study, 984 HCV-uninfected controls, 221 infected individuals with spontaneous HCV clearance, and 456 with persistent HCV infection were enrolled. Rs28362491 and rs72696119 were genotyped using the ABI TaqMan allelic discrimination assay. The functional annotation of the identified single nucleotide polymorphisms (SNPs) were further evaluated by bioinformatics analysis., Results: Significant differences were observed among the three groups (P < 0.001) in terms of the frequency of rs28362491 SNP. In logistic regression analysis, rs28362491-ATTG deleted (D) was associated with a significantly increased risk of HCV infection compared to the major-type rs28362491-ATTG inserted (I) (dominant model: adjusted OR = 1.332, 95% CI = 1.059-1.674, P = 0.014; additive model: adjusted OR = 1.181, 95% CI = 1.021-1.367, P = 0.025), after adjusting for age, gender, and route of infection. Based on the in silico prediction, the RegulomeDB score for SNP rs28362491 was 3a, indicating that it can potentially regulate the transcription and expression of NFKB1 gene., Conclusion: NFKB1 rs28362491-D allele was functionally associated with the increased risk of susceptibility to HCV infection in the Chinese Han population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To explore the association between nuclear factor kappa-light-chain-enhancer of activated genetic polymorphisms in B cells ( NF-κB ) and the HCV susceptibility, among the Chinese population. Methods: A total of 1 679 participants were enrolled; including 503 drug users and 1 176 other participants at risk under the exposure for blood. By using the logistic regression analysis, related risk factors for HCV infection among subjects were analyzed. Two NF-κB pathway variants, NF-κB1 rs72696119 and REL rs13031237 were then genotyped by TaqMan assay method. Logistic regression analysis was performed to analyze the association between gene polymorphisms and the susceptibility on HCV. Results: Among the drug users, women ( OR =0.408, 95 %CI : 0.308-0.767) appeared to be associated with the decreased risk for HCV infection, while factors as drug injection ( OR =8.817, 95 %CI : 5.577-13.937) and the duration of drug-intake >5.5 years ( OR =2.891, 95 %CI : 1.824-4.583) were associated with the increased risk for HCV infection. Among the participants who had been exposed to blood, women ( OR =3.431, 95 %CI : 2.360-4.988) were associated with the increased risk for HCV infection, while the levels of education beyond elementary school ( OR =0.613, 95 %CI : 0.429-0.876) were associated with the decreased risk for HCV infection. Compared to the reference NF-κB1 rs72696119 CC genotype, the carriage of GG genotype was associated with an increased risk of susceptibility on HCV ( OR =1.412, 95 %CI : 1.035-1.927) among the total study population. Results from the interaction analysis showed that there was no interactive effects appeared between rs72696119 and route of infection, or between rs72696119 and gender among the total population under study (all P >0.05). Conclusion: NF-κB1 polymorphism rs72696119 and related factors seemed associated with the susceptibility to HCV infection among high-risk Chinese populations.

Aim: To explore the association of CCL3 (rs1063340) and CCL4 (rs1049807) polymorphisms with hepatitis C virus (HCV) clearance and sustained virologic response (SVR)., Methods: Two populations were enrolled in the current study; one was a general population including 1585 untreated individuals, with HCV infection and the other was a treatment population comprising 353 HCV-infected patients treated with pegylated interferon-α and ribavirin (pegIFN-α/RBV). Two single nucleotide polymorphisms (SNPs) were genotyped, and the relationship between HCV clearance and treatment outcome was analysed., Results: The general population comprised 995 persistent HCV cases (both HCV RNA and anti-HCV were positive) and 590 spontaneous clearance cases (HCV RNA was negative, but anti-HCV was positive). An association between the SNPs and HCV clearance was not found in our study. The treatment population consisted of 235 patients who achieved SVR and 118 non-responders. Variants of both SNPs (rs1063340-C and rs1049807-G) were associated with a reduction in SVR following IFN treatment (dominant model: P = 0.026 for rs1063340 and P = 0.048 for rs1049807). In addition, the ancestral alleles of rs1063340 and rs1049807 increased the likelihood of virus clearance by 62% compared to both the derived and minor alleles of the two SNPs (P = 0.040).The interaction analysis showed that the level of glucose interacted with the association of rs1063340 and SVR., Conclusions: Our results suggested that genetic variants at the CCL3 and CCL4 loci may be marker SNPs for risk of HCV treatment outcome., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Polymorphisms within NF-κB pathway genes may be linked to hepatitis C virus (HCV) infection susceptibility and outcomes. We investigated the associations between single nucleotide polymorphisms (SNPs) in NF-κB and the susceptibility as well as resolution of HCV infection. A Chinese population, including 1125 uninfected control cases, 558 cases with spontaneous viral clearance and 898 cases with persistent HCV infection, was genotyped for four SNPs (rs11820062, rs230530, rs1056890 and rs3774963) using a TaqMan assay. Our logistic analyses indicate that the subjects carrying RelA rs11820062 A allele had a significantly increased risk of HCV susceptibility (P Bonferroni  < 0.003125 in a dominant or additive model). In stratified analysis, the increased risk associated with rs11820062 A allele on HCV susceptibility remained in some case subgroups. This study demonstrates that a genetic variant involved in the NF-κB pathway gene (rs11820062 A allele) is associated with an increased HCV susceptibility within a high-risk Chinese population.

Background: Recently, human leukocyte antigen (HLA) class-II gene polymorphisms have been reported to be related to Hepatitis C virus (HCV) infection and chronicity. The objective of this study was to explore the relationship of HLA-DP rs9277535 and HLA-DQ rs7453920 with the outcomes of HCV infection., Methods: The rs9277535 and rs7453920 were genotyped in 370 subjects with chronic HCV infection, 194 subjects with spontaneous HCV clearance, and 973 subjects with non-HCV infection from the Chinese population using the ABI TaqMan allelic discrimination assay., Results: Logistic regression analyses showed that the minor allele A of rs7453920 significantly increased the susceptibility of HCV infection in dominant model (adjusted OR = 1.33, 95% CI: 1.04-1.71, P = 0.026) and additive models (adjusted OR = 1.30, 95% CI: 1.06-1.60, P = 0.012). Rs9277535 A allele significantly increased the risk of chronic HCV infection in dominant model (adjusted OR = 1.52, 95% CI: 1.01-2.28, P = 0.046). Haplotype AA showed a higher risk of HCV infection than the most frequent haplotype GG (adjusted OR = 1.37, 95% CI: 1.05-1.78, P = 0.018)., Conclusion: The HLA-DQ rs7453920 and -DP rs9277535 mutations were significantly associated with HCV infection susceptibility and chronicity, respectively.

Background: Chemokine genes play an essential role in both spontaneous clearance in acute infection and therapy of HCV. We investigated whether several CXC family-related genes associated with HCV spontaneous clearance and response to treatment., Methods: The current study genotyped four SNPs, respectively are CXCR6 rs2234358, CXCL12 rs1801157, CXCL9 rs10336, rs3733236 to assess their associations with HCV spontaneous clearance and response to treatment in a two stage study (668 chronic and 400 resolvers in discovery group, meanwhile 333 chronic and 199 resolver in replication group), and a treatment cohort of HCV with 282 patients., Results: We found that the CXCR6 rs2234358 was associated with HCV spontaneous clearance in Chinese Han population (dominant model: adjusted OR=1.62, 95%CI: 1.30-2.01; additive model: adjusted OR=1.43, 95%CI: 1.20-1.70). Patients carrying GT/TT genotypes had increased sustained virological response compared with patients carrying the GG genotype (dominant model: adjusted OR=2.23, 95%CI: 1.26-3.95)., Conclusion: These results suggest that CXCR6 rs2234358 is associated with spontaneous clearance of HCV and response to IFN-α/RBV therapy, which may be identified as a predictive marker in Chinese Han population of HCV., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recent many studies indicated a novel dinucleotide variant in ss469415590 (TT vs. ΔG) of interferon-λ 4 (IFNL4) gene strongly associated with hepatitis C virus clearance. To evaluate the impact and clinical usefulness of IFNL4 ss469415590 genotype on predicting both spontaneous HCV clearance and response to therapy in Chinese population, we genotyped 795 chronic HCV carriers, 460 subjects with HCV natural clearance and 362 patients with pegylated interferon-α and ribavirin (PEG IFN-α/RBV) treatment. IFNL4 ss469415590 variant genotypes significantly decreased host HCV clearance, both spontaneous (dominant model: OR = 0.50, 95% CI = 0.36-0.71) and IFN-α induced (dominant model: OR = 0.32, 95% CI = 0.18-0.56). Multivariate stepwise analysis indicated that ss469415590, rs12979860, the level of baseline HCV RNA and platelet were as independent predictors for sustained virological response (SVR). But the area under the ROC curve (AUC) was only 0.58 for ss469415590, and it was elevated to 0.71 by adding rs12979860, baseline HCV RNA and platelet in the prediction model of SVR. Therefore, these findings underscore that although genetic factors of host and pathogen were commonly important during HCV clearance, ss469415590 may be also a strongly predictive marker in the Chinese population., Competing Interests: The authors declare no competing financial interests.

Vitamin D has been considered as an immune modulator, and exerted the effect through the vitamin D receptor (VDR). This study investigated the associations of single-nucleotide polymorphisms (SNPs) of VDR with the outcomes of Hepatitis C virus (HCV) infection. Three SNPs (rs2228570, rs757343 and rs739837) were genotyped by TaqMan assay among Chinese population, including 538 HCV spontaneous clearance subjects, 834 persistent infection subjects and 1030 uninfected subjects. Binary logistic analyses were used to control the effects of confounding factors. The results showed that subjects with the rs757343 A allele and rs739837 A allele had the significantly reduced risk of HCV susceptibility (all PBonferroni<0.05 in dominant/additive model). In the stratified analysis, the protection of rs757343 A allele and rs739837 A allele against HCV infection remained effective in some subgroups. In addition, patients carrying rs739837 CA genotype were less prone to develop persistent infection (PBonferroni=0.033) and such effect still work in several subgroups in the stratified analysis. Furthermore, haplotype analysis indicated that when compared with the most frequent GC haplotype, the haplotype carrying AA (odds ratio (OR)=0.66, 95% confidence interval (CI)=0.56-0.78) and GA (OR=0.64, 95% CI=0.47-0.85) suggested a protective effect. Our findings indicated that the polymorphisms of VDR are associated with the outcomes of HCV infection among Chinese population.

Limited information is available on the prevalence of hepatitis C virus (HCV) in the general population in China. A community-based epidemiological study was conducted in three counties in eastern China. A total of 149 175 individuals were investigated in 60 communities in three counties in Jiangsu province, eastern China, of whom 1175 subjects [0·79%, 95% confidence interval (CI) 0·74-0·83] were HCV antibody positive. The prevalence was low in children (0·09%, 95% CI 0·04-0·17), but increased progressively from adolescents (0·20%, 95% CI 0·15-0·28) to adults aged ⩾21 years (95% CI 0·15-1·64). Women had a higher prevalence of HCV infection than men in most age groups. In a multilevel regression analysis, age, sex, education, occupation, blood transfusion [odds ratio (OR) 2·91, 95% CI 1·09-5·37], invasive testing (OR 1·28, 95% CI 1·14-1·61), and dental therapy (OR 2·27, 95% CI 1·41-3·42) were associated with HCV infection. In conclusion, although the prevalence of HCV in this population was lower than reported from national levels, the total reservoir of infection is significant and warrants public health measures, such as health education to limit the magnitude of the problem.

Human leukocyte antigen (HLA) class II molecule influences host antigen presentation and anti-viral immune response. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) within HLA class II gene were associated with different clinical outcomes of hepatitis C virus (HCV) infection. Three HLA class II SNPs (rs3077, rs2395309 and rs2856718) were genotyped by TaqMan assay among Chinese population, including 350 persistent HCV infection patients, 194 spontaneous viral clearance subjects and 973 HCV-uninfected control subjects. After logistic regression analysis, the results indicated that the rs2856718 TC genotype was significantly associated with the protective effect of the HCV natural susceptibility (adjusted OR: 0.712, 95% CI: 0.554-0.914) when compared with reference TT genotype, and this remained significant after false discovery rate (FDR) correction (p = 0.024). Moreover, the protective effect of rs2856718 was observed in dominant genetic models (adjusted OR: 0.726, 95% CI: 0.574-0.920), and this remained significant after FDR correction (p = 0.024). In stratified analysis, a significant decreased risk was found in rs2856718C allele in the male subgroup (adjusted OR: 0.778, 95% CI: 0.627-0.966) and hemodialysis subgroup (adjusted OR: 0.713, 95% CI: 0.552-0.921). Our results indicated that the genetic variations of rs2856718 within the HLA-DQ gene are associated with the natural susceptibility to HCV infection among the Chinese population.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and the varied outcomes of the infection depend on both viral and host factors. We have demonstrated that the HCV alternate reading frame protein (F protein) is related to Th1/Th2 bias which is involved in virus persistence in chronic hepatitis C (CHC) patients. The purpose of this study was to test the hypothesis that genetic variants of TBX21 (T cell specific T-box transcription factor) were associated with the outcomes of HCV infection and F protein generation. Three single nucleotide polymorphisms (SNPs) (rs17250932, rs2074190, rs4794067) in the TBX21 gene were genotyped in a case-control study in a cohort of a high-risk group, including 354 healthy controls and 747 CHC patients (190 anti-F protein antibody seronegative patients and 557 anti-F protein antibody seropositive patients). Results showed that the rs4794067 C allele in the TBX21 promoter was significantly more common in CHC patients (OR = 1.335, 95% CI = 1.058-1.684, P = 0.015), exceptionally in anti-F protein seropositive patients (OR = 1.547, 95% CI = 1.140-2.101, P = 0.005), compared with healthy controls. And the risk effect was also significantly high in patients with HCV 1b genotype and mild fibrosis (P = 0.021, P = 0.010, respectively). Compared with the most frequent haplotype TAT, haplotype analysis showed that the distribution of TAC was significantly different between the chronic HCV carrier group and the healthy group, and so was the anti-F antibody seronegativity group and the anti-F antibody seronegativity group (all P < 0.001). Our results suggested that TBX21 variants may be involved in the etiology of this disease.

Hepatitis C virus (HCV) has different clinical and biological characteristics in women versus men, which suggests the potential involvement of estrogen. Estrogen signaling is mediated by the estrogen receptor, and genetic variations in the estrogen receptor gene might affect the pathology of HCV infection. We performed logistic regression analysis to explore the associations between rs1256049, rs4986938 and rs944459 polymorphisms of the estrogen receptor 2 gene (ESR2) and HCV infection outcomes. The variant A allele of rs4986938 was associated with an increased HCV infection susceptibility in the males (additive model: adjusted OR=1.493, P=0.010) and a significantly reduced risk of HCV infection in the female subgroup (GA vs. GG: adjusted OR=0.710, P=0.012; dominant model: adjusted OR=0.686, P=0.004; additive model: adjusted OR=0.703, P=0.002). In addition, females carrying the rs4986938 AA genotype appeared to clear HCV spontaneously more readily (adjusted OR=0.237, P=0.011), and additive model analyses showed that each additional allele contributed a decreased risk of approximately 34% for HCV chronicity (adjusted OR=0.659, P=0.006). Furthermore, a significant multiplicative interaction between the combined rs1256049 and rs4986938 genotypes was found to decrease HCV infection risk (adjusted OR=0.583, P=3.000×10(-4)). The area under the curve, based on the model and including age, gender, HCV genotypes and the three SNPs, was significantly related to the clearance of HCV (P=0.003). We provide here the first report that rs4986938 in the ESR2 gene played a potential sex-specific role in the etiology of HCV infection in a high-risk Chinese Han population, suggesting that ESR2 is a candidate susceptibility gene for HCV infection and viral clearance., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Toll-like receptors 7 (TLR7) play a crucial role in provoking an immune response in HCV infection. We aimed to investigate whether single nucleotide polymorphisms (SNPs) of TLR7, including rs179009, rs179010 and rs179012, affect the outcomes of HCV infection among the Chinese population. A total of 1767 Chinese Han individuals were enrolled. The distribution of SNP frequencies among three groups with different outcomes of HCV infection was assessed, including healthy controls, cases with spontaneous clearance and cases with viral persistence. Then TLR7 mRNA expression and the production of IFN-α and IL-6 after TLR7 agonist Imiquimod stimulation in vitro were determined. Our results suggested that rs179009 GG genotype was significantly associated with a higher risk of the susceptibility to HCV infection among female subjects (OR=2.42, 95% CI=1.24-4.71, P=0.01). Haplotype GCG was significantly associated with a high risk for HCV susceptibility (OR=1.50, 95% CI=1.11-2.03, P=0.01) as compared with the reference haplotype ACG among females. In the functional research of rs179009, a lower IFN-α level was observed in GG genotype than in AA genotype (P=0.032). Our data indicate that TLR7 rs179009 GG genotype and haplotype GCG were associated with an increased risk of the susceptibility to HCV infection among Chinese females, which may be due to the impaired IFN-α response., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Toll-like receptor 7 (TLR7) senses hepatitis C virus (HCV) infection and drives the host specific innate and adaptive immune response. The aim of this study was to estimate the distributions of TLR7 single nucleotide polymorphisms (SNPs), including rs179019 and rs3853839, as well as the effect of TLR7 gene variants on TLR7 mRNA expression and cytokine production in response to TLR7 agonist in vitro. TLR7 SNP genotyping was performed among a Chinese sample population of 418 patients with persistent HCV infection, 317 patients with HCV spontaneous clearance, and 989 healthy controls. TLR7 mRNA expression and TLR7-specific IFN-α and IL-6 secretion in peripheral blood mononuclear cells, derived from 60 healthy individuals in vitro, were then quantified. We identified the association of TLR7 rs3853839C allele, haplotype CC and haplotype AC (rs179019/rs3853839) with protection against HCV persistence in Chinese females (OR=0.49, 95% CI=0.29-0.81, P=0.01 for rs3853839 GC; OR=0.29, 95% CI=0.11-0.75, P=0.01 for rs3853839 CC; OR=0.51, 95% CI=0.38-0.77, P<0.01 for haplotype CC; OR=0.29, 95% CI=0.10-0.88, P=0.03 for haplotype AC). In addition, the rs3853839 CC genotype among female carriers had significantly low TLR7 mRNA expression (P=0.006 for GG vs. CC, P=0.021 for GC vs. CC), along with decreased IFN-α (P=0.002 for GG vs. CC, P=0.021 for GC vs. CC) and increased antiviral IL-6 production (P=0.002 for GG vs. CC, P=0.030 for GC vs. CC), after treatment with Imiquimod in vitro. The cytokine profile among rs3853839 CC genotype female carriers may indicate a pronounced protective effect against persistent HCV infection. The functional polymorphism of TLR7 rs3853839C allele was found to be sex-specific and associated with protection against HCV persistence among Chinese females, which may be due to specific IFN-α and IL-6 secretion profiles., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The purpose of this study was to test the hypothesis that genetic variants of estrogen receptor α (ERα) are associated with the outcomes of hepatitis C virus (HCV) infection. We genotyped the seven single nucleotide polymorphisms (SNPs) (rs2077647, rs9340799, rs2234693, rs1801132, rs9322354, rs2228480 and rs3798577) of ERα and conducted a case-control study in a high-risk Chinese population, including 429 HCV spontaneous clearance cases, 880 persistent infection cases and 1,174 uninfected controls. The C allele of rs2234693 was significantly associated with increased susceptibility to HCV infection [dominant model: adjusted odds ratio (OR) = 1.377, 95% confidence interval (CI) =1.126-1.778], and the risk effect remained significant among the younger (≤55 years) and hemodialysis subjects (all P < 0.007). The other three SNPs variant genotypes also showed significant correlation with elevated risk of HCV infection in different strata (rs2077647 in males; rs9340799 in blood donors; rs1801132 in younger subjects; all P < 0.007). It was also discovered that carriage of rs2228480 A allele was more prone to develop persistent HCV infection (dominant model: adjusted OR = 1.203, 95% CI = 1.154-1.552), and the risk effect was more evident in females and blood donors (all P < 0.007). Haplotype analyses (rs2077647, rs9340799 and rs2234693) showed that, compared with the most frequent haplotype TAT, CAC played a risk effect in subgroups of younger (P = 3.24 × 10(-3)) and male (P = 5.51 × 10(-4)), whereas CAT expressed a protective effect in females (P = 2.27 × 10(-4)) for HCV infection susceptibility. We first report that these SNPs (rs2077647, rs9340799, rs2234693, rs1801132 and rs2228480) in ERα can influence the outcomes of HCV infection in a high-risk Chinese population.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and the varied outcomes of the infection depend on both viral and host factors. We have demonstrated that the HCV alternate reading frame protein (F protein) is related to Th1/Th2 bias which is involved in virus persistence in chronic hepatitis C (CHC) patients. The purpose of this study was to test the hypothesis that genetic variants of TBX21 (T cell specific T-box transcription factor) were associated with the outcomes of HCV infection and F protein generation. Three single nucleotide polymorphisms (SNPs) (rs17250932, rs2074190, rs4794067) in the TBX21 gene were genotyped in a case-control study in a cohort of a high-risk group, including 354 healthy controls and 747 CHC patients (190 anti-F protein antibody seronegative patients and 557 anti-F protein antibody seropositive patients). Results showed that the rs4794067 C allele in the TBX21 promoter was significantly more common in CHC patients (OR = 1.335, 95 % CI = 1.058-1.684, P = 0.015), exceptionally in anti-F protein seropositive patients (OR = 1.547, 95 % CI = 1.140-2.101, P = 0.005), compared with healthy controls. And the risk effect was also significantly high in patients with HCV 1b genotype and mild fibrosis ( P = 0.021, P = 0.010, respectively). Compared with the most frequent haplotype TAT, haplotype analysis showed that the distribution of TAC was significantly different between the chronic HCV carrier group and the healthy group, and so was the anti-F antibody seronegativity group and the anti-F antibody seronegativity group (all P < 0.001). Our results suggested that TBX21 variants may be involved in the etiology of this disease. [ABSTRACT FROM AUTHOR]