Risk Factors For Chronic Hepatitis Research Articles

Predicting Immune Flares in Untreated Chronic Hepatitis B Patients Using Novel Risk Factors and the FLARE-B Score.

Risk factors of chronic hepatitis B (CHB) immune flares are poorly understood. The primary aim of this study was to discover predictors of the CHB flare in non-cirrhotic, untreated CHB patients and develop a simple risk-stratifying score to predict the CHB flare. The secondary aim was to compare different machine learning methods for prediction. A retrospective cohort of untreated, non-cirrhotic CHB patients with normal baseline ALT was followed up over time until an immune flare as defined by ALT twice the upper limit of normal. Statistical learning and machine learning algorithms were used to develop predictive models using baseline variables. Bootstrap validation was used to internally validate the models. Of 405 patients (median age 44y; 41% male, 10% HBeAg positive), 67 (17%) experienced an immune flare by 5 years (annual incidence 4.0%). Predictors of flare included raised serum globulin, younger age, HBeAg positive status, higher viral load and raised liver stiffness. A simple predictive model "FLARE-B" had optimism-adjusted 1, 3 and 5-year AUCs of 0.813, 0.728 and 0.702, respectively. The random survival forest algorithm had the highest optimism-adjusted AUCs of 0.861, 0.766 and 0.725, respectively. New, novel predictors of the CHB flare include a raised serum globulin and possibly raised liver stiffness and the absence of liver steatosis. FLARE-B can be used to risk-stratify individuals and potentially guide personalized management strategies such as monitoring schedules and proactive antiviral treatment in high-risk patients.

Genetic variants of Nuclear Factor-Kappa B were associated with different outcomes of Hepatitis C virus infection among Egyptian patients.

Hepatitis C virus (HCV) is a major risk factor for chronic hepatitis and hepatocellular carcinoma (HCC). Nuclear factor kappa B (NF-κB) is a transcription factor that functions in health and disease. Genetic variants of the NF-κB gene can affect its function and are associated with chronic inflammatory changes and malignant transformation. This case-control study is aimed to determine the possible association between NF-κB genetic variants and different outcomes of HCV infection among Egyptian patients. 295 subjects were recruited with allocation of participants in the representative group according to results of serological and molecular tests. Patients in the case group (group A) were further divided into three subgroups; subgroup I, mild chronic HCV, subgroup II, cirrhosis, and subgroup III, HCC subgroups (59 for each subgroup), group B included participants who experienced spontaneous viral clearance (n=59). All were compared to matched healthy control subjects, Group C (n=59). All participants were genotyped for NF-κB polymorphisms, rs11820062 by TaqMan assay and rs28362491 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Risk analysis indicated that subjects carrying the rs11820062 A genotype are more susceptible to HCV infection (OR: 3.1; 95%, CI= 1.4-6.9). Subjects carrying the rs28362491 insertion genotype are at more risk of progression to cirrhosis when compared to healthy-controls and patients with mild chronic HCV (OR:7.7; 95% CI=2.4-24.3 and OR:5.1, 95% CI= 1.7-15.7, respectively) and also are at more risk of developing HCC when compared to healthy controls (OR:2.6; 95% CI= 0.94-7.3). Polymorphisms affecting NF-κB different genes would modulate HCV infection susceptibility and clinical disease progression among Egyptian patients.

Conventional and genetic risk factors for chronic Hepatitis B virus infection in a community-based study of 0.5 million Chinese adults

Despite universal vaccination of newborns, the prevalence of chronic hepatitis virus B (HBV) infection and the associated disease burden remain high among adults in China. We investigated risk factors for chronic HBV infection in a community-based study of 512,726 individuals aged 30–79 years recruited from ten diverse areas during 2004–2008. Multivariable logistic regression was used to estimate odds ratios (ORs) of hepatitis B surface antigen (HBsAg) positivity recorded at baseline by sociodemographic and lifestyle factors, and medical history. In a random subset (n = 69,898) we further assessed the association of 18 single nucleotide polymorphisms (SNPs) previously shown to be associated with HBsAg positivity and development of chronic liver disease (CLD) (1600 cases). Several factors showed strong associations with HBsAg positivity, particularly younger age (< 40 vs. ≥ 60 years: OR 1.48, 95% CI 1.32–1.66), male sex (1.40, 1.34–1.46) and urban residency (1.55, 1.47–1.62). Of the 18 SNPs selected, 17 were associated with HBsAg positivity, and 14 with CLD, with SNPs near HLA-DPB1 were most strongly associated with both outcomes. In Chinese adults a range of genetic and non-genetic factors were associated with chronic HBV infection and CLD, which can inform targeted screening to help prevent disease progression.

MiR-155 T/A (rs767649) and miR-146a A/G (rs57095329) single nucleotide polymorphisms as risk factors for chronic hepatitis B virus infection among Egyptian patients.

Genetic variants in microRNAs (miRNAs) can alter the miRNAs expression and/or function, accordingly, affecting the related biological pathways and disease risk. Dysregulation of miR-155 and miR-146a expression levels has been well-described in viral hepatitis B (HBV). In the current study, we aimed to assess rs767649 T/A and rs57095329 A/G polymorphisms in miR-155, and miR-146a genes, respectively, as risk factors for Chronic HBV (CHBV) in the Egyptian population. Also, we aimed to do in silico analysis to investigate the molecules that primarily target these miRNAs. One hundred patients diagnosed as CHBV and one hundred age and sex-matched controls with evidence of past HBV infection were genotyped for miR-155 (rs767649) and miR-146a (rs57095329) using real-time polymerase chain reaction. The rs767649 AT and AA genotypes in CHBV patients confer four folds and ten folds risk respectively, as compared to control subjects [(AOR = 4.245 (95%CI 2.009–8.970), p<0.0001) and AOR = 10.583 (95%CI 4.012–27.919), p<0.0001, respectively)]. The rs767649 A allele was associated with an increased risk of developing CHBV (AOR = 2.777 (95%CI 1.847–4.175), p<0.0001). There was a significant difference in the frequency of rs57095329 AG and GG genotypes in CHBV patients compared to controls. AG and GG genotypes showed an increase in the risk of developing CHBV by about three and six folds respectively [AOR = 2.610 (95%CI 1.362–5.000), p = 0.004] and [AOR = 5.604 (95%CI 2.157–14.563), p<0.0001].We concluded that rs57095329 and rs767649 SNPs can act as potential risk factors for the development of CHBV in the Egyptian population.

Sibling status, home birth, tattoos and stitches are risk factors for chronic hepatitis B virus infection in Senegalese children: A cross‐sectional survey

Sub-Saharan Africa's hepatitis B virus (HBV) burden is primarily due to infection in infancy. However, data on chronic HBV infection prevalence and associated risk factors in children born post-HBV vaccination introduction are scarce. We estimated hepatitis B surface antigen (HBsAg) prevalence and risk factors in Senegalese children born during the HBV vaccination era. In 2018-2019, a community-based cross-sectional survey was conducted in Senegal among children born between 2004 and 2015 (ie after the three-dose HBV vaccine series was introduced (2004) but before the birth dose's introduction (2016)). HBsAg-positive children were identified using dried blood spots. A standardized questionnaire collected socioeconomic information. Data were age-sex weighted and calibrated to be representative of children living in the study area. Risk factors associated with HBsAg positivity were identified using negative binomial regression. Among 1,327 children, 17 were HBsAg-positive (prevalence=1.23% (95% confidence interval [CI] 0.61-1.85)). Older age (adjusted incidence-rate ratio [aIRR] 1.31 per one-year increase, 95% CI 1.10-1.57), home vs healthcare facility delivery (aIRR 3.55, 95% CI 1.39-9.02), stitches (lifetime) (aIRR 4.79; 95% CI 1.84-12.39), tattoos (aIRR 8.97, 95% CI 1.01-79.11) and having an HBsAg-positive sibling with the same mother (aIRR 3.05, 95% CI 1.09-8.57) were all independently associated with HBsAg positivity. The low HBsAg prevalence highlights the success of the Senegalese HBV vaccination program. To further reduce HBV acquisition in children, high-risk groups, including pregnant women and siblings of HBsAg-positive individuals, must be screened. Vital HBV infection prevention measures include promoting delivery in healthcare facilities, and increasing awareness of prevention and control procedures.

Association of genetic polymorphism of BCL-2 (rs2279115) with susceptibility to HCV-related hepatocellular carcinoma.

Hepatitis C virus (HCV) infection is the main risk factor for chronic hepatitis (CHC), liver cirrhosis, and hepatocellular carcinoma (HCC). B cell lymphoma-2 (BCL-2) prevents apoptosis, and its overexpression could promote cancer cell survival. The purpose of this study is to evaluate the association of Bcl-2 gene polymorphism (rs2279115) and HCV-related HCC susceptibility. Two hundred and seventy individuals included in this case-control were divided into three groups. Group I: It included 90 apparently healthy subjects as control. Group II: It includes 90 patients with chronic HCV hepatitis. Group III: It includes 90 patients with HCC with positive HCV. Bcl-2 gene polymorphism (rs2279115) C > A genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). There are significantly higher incidence of CA and AA genotypes in HCV patients with HCC compared with those without HCC (OR 2.3, %CI (1.2-4.6), P = 0.01 and OR 5.7, %CI (2.4-13.8), respectively) and compared with control group (OR 2.9, %CI (1.5-5.8), P = 0.002 and OR 7.1, %CI (2.9-17.4), P < 0.001, respectively), while no significant difference between the control and HCV patients without HCC groups (OR 1.2, %CI (0. 7-2.4), P = 0.48, for CA, and OR 1.2, %CI (0.4-3.3), P = 0.67, for AA).The frequency of A allele was highly significantly overrepresented in the HCC group in comparison to HCV group (53.3% versus 30.6%, P < 0.001) and control group (53.3% versus 27.2%, P < 0.001) but no significant difference (p = 0.49) between control group and HCV patients. This study demonstrated that Bcl-2 gene polymorphism (rs2279115) was associated with increased susceptibility to HCV-related HCC.

The association between metabolic syndrome and Hepatitis C virus infection in the United States.

Hepatitis C virus (HCV) infection is the prevalent risk factor for chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. The association between metabolic syndrome (MetS) and HCV infection has not been studied effectively, particularly among different ethnic/racial groups in the US. A retrospective cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (1999-2014). Unadjusted and adjusted associations were summarized using the prevalence ratio (PR) and 95% confidence interval (CI) after exploring possible interactions. In the overall population, MetS was significantly associated with HCV infection with an interaction of age. After adjusting for all potential confounders, MetS was found to be significantly associated with HCV among non-obese and younger adults of age less than 60years (PR 1.67, 95% CI 1.21-2.30, p = 0.002). MetS was also associated with an increased prevalence of HCV in each racial/ethnic group, while the association was strongly modified by age and obesity status of the subjects in different ethnic/racial groups. MetS or its components are associated with an increased prevalence of HCV in some sub-populations of all ethnic/racial groups in the US. A better understanding of the pathophysiology of MetS associated with HCV is important as MetS may have a role in HCV infection treatment outcomes.

Immune suppression in chronic hepatitis B infection associated liver disease: A review.

Hepatitis B virus (HBV) infection is one the leading risk factors for chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular cancer (HCC), which are a major global health problem. A large number of clinical studies have shown that chronic HBV persistent infection causes the dysfunction of innate and adaptive immune response involving monocytes/macrophages, dendritic cells, natural killer (NK) cells, T cells. Among these immune cells, cell subsets with suppressive features have been recognized such as myeloid derived suppressive cells(MDSC), NK-reg, T-reg, which represent a critical regulatory system during liver fibrogenesis or tumourigenesis. However, the mechanisms that link HBV-induced immune dysfunction and HBV-related liver diseases are not understood. In this review we summarize the recent studies on innate and adaptive immune cell dysfunction in chronic HBV infection, liver fibrosis, cirrhosis, and HCC, and further discuss the potential mechanism of HBV-induced immunosuppressive cascade in HBV infection and consequences. It is hoped that this article will help ongoing research about the pathogenesis of HBV-related hepatic fibrosis and HBV-related HCC.

SAT-212-Treatment with mTOR inhibitors is an independent risk factor for chronic hepatitis E in transplant patients with increased transaminases levels

SAT-212-Treatment with mTOR inhibitors is an independent risk factor for chronic hepatitis E in transplant patients with increased transaminases levels

341 Structure Proteins of Hepatitis C Induce miR-494-3p and miR942-3p Expression

Hepatitis C virus (HCV) infection, estimated in 3% of the world’s population, remains a major risk factor for chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Based on the recognition of single-stranded viral RNA, TLR7 and TLR8 have been suggested to play important roles in antiviral immune responses to HCV. The miRNAs, endogenously expressed small noncoding RNAs, are known to promote mRNA degradation and block protein translation. In the present study, the specific candidate miRNAs that influence HCV protein-modulated TLR7/8 expression and subsequent signal modulation were investigated. miRNA microarray analysis was performed to screen for the miRNAs expression in HCV structure proteins (core, E1, and E2) stably transfected HepG 2 cells, and miRBase was used to predict the interaction between these miRNAs and TLR7/8 gene. miR-494-3p and miR942-3p were identified and validated. A total of 100 serum samples (30 samples from controls, 70 samples from HCV-infected patients) were collected. The levels of the two, miR-494-3p and miR942-3p, were then detected by probe-based stem-loop quantitative reverse-transcriptase PCR. We found that the expression of serum miR-494-3p and miR942-3p was distinctly increased in HCV patients compared with controls (mean ± SEM: 917.7 ± 192.2 vs 32.5 ± 14.2, P < .001 and 1615.0 ± 516.3 vs 8.0 ± 5.4, P < .001). In addition, interferon treatment significantly decreased miR942-3p expression in HCV patients (mean ± SEM: 67200 ± 55000 vs 263400 ± 195900, P = .03). The expression of miR-494-3p and miR942-3p in serum were significantly up-regulated in patients with HCV infection. However, the modulation mechanisms of miR494-3p and miR942-3p on TLR7/8 need further investigation.

Adiponectin levels and insulin resistance among patients with chronic hepatitis C

Chronic hepatitis C virus (HCV) infection is associated with insulin resistance (IR), rapid disease progression, and decreased virological response to antiviral treatment. In addition, obesity is a risk factor for chronic hepatitis C evolution and is associated with IR. As adiponectin is an adipokine that is associated with obesity and IR, this study aimed to investigate serum levels of adiponectin among patients with HCV infection and IR. Thirty-three patients with untreated HCV infection underwent testing of serum adiponectin levels (capture ELISA) and were compared to 30 healthy subjects with similar body mass indexes (BMI). Data were also obtained for several homeostatic model assessment (HOMA) indexes: HOMA-IR, HOMA-β, and HOMA-adiponectin. Patients with HCV infection had higher adiponectin levels, which predominantly were observed among women. Hyperadiponectinemia was not associated with high BMI. Patients with HCV infection had higher HOMA-IR and HOMA-β values, although no difference was observed for HOMA-adiponectin. Patients with HCV infection and overweight/obese status had higher HOMA-IR values, although no association was observed for adiponectin levels. Hyperadiponectinemia and IR were not influenced by HCV load or liver fibrosis. The predictors of IR were BMI, glycemia, and serum levels of insulin and non-high-density lipoprotein cholesterol, but not adiponectin levels. Thus, patients with chronic hepatitis C have significant metabolic alterations (hyperadiponectinemia and high HOMA-IR values) that are independent of HCV viremia and liver fibrosis. Among these patients, HOMA-IR but not HOMA-adiponectin was appropriate for diagnosing IR.

Prevalence and Risk Factors of Chronic Hepatitis B and C Virus Infection in the Immigrant Populations of the Twin Cities Metro Area, Minnesota, United States

Introduction: HBI-Minnesota is a non-profit organization that provides free viral hepatitis testing, screening for metabolic risk factors, education and linkages to care for underserved communities. Methods: Between February 2016 and April 2017, HBI-Minnesota screened 624 individuals in the Twin Cities (St. Paul and Minneapolis) for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Participants also underwent serum glucose and plasma cholesterol testing. Results: Mean age was 52 + 10 years. Majority (56%) were males, and 64% were foreign-born (17% Vietnam, 17% Laos, 8% Burma, 22% Africa, and 36% others). A total of 4.2% of participants had evidence of chronic HBV. A total of 43% had no evidence of immunity against HBV and should be vaccinated. A total of 1.4% have positive HCV antibody. Table-1 summarizes risk factors of positive HBV or HCV testing. Elevated fasting serum glucose (>110 mg/dL) was seen in 7.8%, while 12.3% had elevated total cholesterol (>190 mg/dL).Table: Table. HBI-Minnesota Screening for Liver Disease summary descriptives table by groups of ‘Hepatitis'Conclusion: HBV and HCV infections are prevalent in the immigrant populations in the Twin Cities Metro Area of Minnesota. Education about viral hepatitis testing and vaccination should be encouraged and supported.

Risk Factors for Chronic Hepatitis C Treatment Relapse with Sequence Based Genotyping among Egyptian Relapse Patients

Background: Chronic Hepatitis C Virus (CHCV) infection in Egypt is a major health problem with a record of being the highest prevalence all over the world with a high incidence of new cases and relapses. Objectives: To monitor treatment response during and post therapy in Egyptian patients and to identify the factors that raises the risk of relapse including HCV genotypes distribution among relapsed patients. Methodology: A total of 125 CHCV-RNA positive patients on two interferon based regimens were followed for 48 week for viral response and relapse to therapy. Genotyping for relapsed patients was determined using direct sequencing and phylogenetic analysis of NS5B region of the HCV genome. Results and Conclusions: Among patients on first regimens, 16 (18.8%) had an overall viral relapse following end of treatment (EOT) and 11 (12.9%) of patients did not respond. In the second group, 8 (20.0%) got viral relapse and 6 (15.0%) were non responders. All relapsed strains fall in the genotype 4a category. In conclusion, old age, higher baseline viral RNA level, histological grade of fibrosis, AFP and APRI are factors that can increase the risk of developing relapse in patients undergo therapy.

Relationship between HLA-DQ Gene Polymorphism and Hepatitis B Virus Infection.

Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB). The association between HBV infection and human leukocyte antigen- (HLA-) DQ polymorphism (rs2856718 and rs7453920) has been demonstrated in other studies; however, the results were controversial or inconclusive. Therefore, to derive a more precise estimation of the association, a meta-analysis was performed. Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of association between HLA-DQ polymorphism (rs2856718 and rs7453920) and HBV infection risk. A total of 11 articles were used to evaluate the effect of the two polymorphisms on risk of HBV infection. The pooled data showed that HLA-DQ rs2856718-G polymorphism showed protection against HBV infection, and rs2856718-A was a risk factor for chronic HBV infection. The pooled risk estimates indicated that HLA-DQ rs7453920-A polymorphism was associated with decreased risk of HBV infection, and rs7453920-G serves as a risk factor in HBV infection. However, these stratified analyses were lacking credibility due to the limitation of correlational study numbers; further investigation on a large population and different ethnicities is warranted.

Risk factors for hepatitis C virus infection in the Colombian Caribbean coast: A case-control study.

An estimated 6.8-8.9 million people are infected with hepatitis C virus in Latin America, of which less than 1% receives antiviral treatment. Studies so far in Colombia have attempted to determine the prevalence of the disease in some risk groups, thus preventing the identification of other factors potentially involved in the spread of the infection. To identify traditional and non-traditional risk factors for chronic hepatitis C in the Colombian Caribbean coast. This was a case-control study (1:3) matched by health care provider and age (± 10 years) conducted at the primary care level of gastroenterology and hepatology outpatient services. All patients with a positive ELISA underwent a confirmatory viral load test. A multivariate logistic regression analysis identified the independent predictors of infection. Blood transfusion (OR=159.2; 95% CI: 35.4-715; p<0.001) and history of hospitalization before 1994 (OR=4.7; 95% CI: 1.3-17.1; p=0.018) were identified as the only two independent predictors of infection. It is necessary to check the reproducibility of these results and to conduct cost-effectiveness studies before recommending their use in the design of new screening strategies.

Identification of novel OCT4 genetic variant associated with the risk of chronic hepatitis B in a Korean population.

Hepatitis B viral infection is a serious risk factor for chronic hepatitis B (CHB), cirrhosis and hepatocellular carcinoma. Recently, several genome-wide association studies (GWASs) have been conducted to identify important genetic variant associated with the risk of CHB. In our previous GWAS, TCF19 was identified as one of the susceptibility genes for CHB risk (P=4.2×10-9 at rs1419881). In order to discover possible additional causal variants around TCF19, we performed an association study by genotyping single nucleotide polymorphisms (SNPs) in OCT4, a nearby gene to TCF19. Nineteen OCT4 genetic variants were selected and genotyped in 3902 subjects (1046 CHB patients and 2856 population controls). Logistic regression analysis revealed that OCT4 rs1265163 showed the most significant association signal for the risk of CHB (OR=1.46, P=4.78×10-12 ). Linkage disequilibrium and conditional analysis confirmed rs1265163 in OCT4 as a novel genetic marker for CHB susceptibility. The genetic risk scores (GRSs) were calculated to visualize the combined genetic effects of all known CHB-associated loci, including OCT4 rs1265163, which had been identified in this study. Individuals with higher cumulative GRSs showed significantly increased ORs. The luciferase activity of rs885952, a tagging SNP of rs1265163, showed that OCT4 promoter activity was significantly different between the wild-type and SNP mutant form (P<.05). This follow-up study to our previous GWAS identified a possible causal genetic variant associated with the risk of CHB, and findings from this study may prove useful in the understanding of genetic susceptibility to CHB.

Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virus infection, clearance and hepatocellular carcinoma development.

Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, genome-wide association studies have identified human leukocyte antigen (HLA)-DP polymorphisms (rs3077 and rs9277535) as a new chronic HBV infection susceptibility locus. Since then, the relationship between HLA-DP polymorphisms and various outcomes of HBV infection has been reported. However, the results have been inconclusive. To derive a more precise estimation of the relationship between HLA-DP polymorphisms and various outcomes of HBV infection, a meta-analysis of 62,050 subjects from 29 case-control studies was performed. We found that rs3077 and rs9277535 in HLA-DP significantly decreased HBV infection risks and increased HBV clearance possibility in a dose-dependent manner. In the subgroup analysis by ethnicity, study design and sample size, significant associations were found for these polymorphisms in almost all comparisons. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and HBV infection outcomes. However, no significant results were observed in HCC development. Our results further confirm that genetic variants in the HLA-DP locus are strongly associated with reduced HBV infection and increased the likelihood of spontaneous viral clearance.

HCV infection-associated hepatocellular carcinoma in humanized mice.

Background and AimsHepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Our aim is to explore molecular changes that underlie HCV infection-associated HCC in a humanized mouse model, in order to identify markers of HCC progression.MethodsLiver proteins from human hepatocyte-engrafted and HCV-infected MUP-uPA/SCID/Bg mice were compared with either uninfected controls or HCV-infected but HCC-negative mice by Western blotting. MicroRNA markers of HCC positive or uninfected mouse liver were analyzed by RT-PCR.ResultsWe describe the depletion of tumor suppressor proteins and induction of oncoproteins and oncogenic microRNAs (oncomiRs) in HCV-infection associated HCC. Similar depletion of PTEN protein in both HCC-positive and HCV-infected but HCC-negative liver suggests that PTEN depletion is an early, precancerous marker of HCC. By contrast, induction of oncoprotein cMyc, oncomiRs (miR21, miR221 and miR141) and inflammatory response proteins correspond to HCC progression.ConclusionsWhile the loss of PTEN is important for the initiation of HCV infection-associated HCC, PTEN depletion by itself is insufficient for tumor progression. Liver tumor progression requires induction of oncoproteins and oncomiRs. Overall, human hepatocyte-engrafted (MUP-uPA/SCID/Bg) mice provide a suitable small animal model for studying the effects of oncogenic changes that promote HCV infection associated HCC.

Association of VARS2‐SFTA2 polymorphisms with the risk of chronic hepatitis B in a Korean population

Hepatitis B virus (HBV) infection is the most serious risk factor for chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma. Recently, several genome-wide association studies (GWASs) identified important variants associated with the risk of CHB in Asian populations. Specifically, our previous GWAS identified the VARS2-SFTA2 gene region as one of the genetic risk loci for CHB. To further characterize this association and to isolate possible causal variants within it, we performed an additional association study by genotyping more SNPs in the vicinity of the VARS2 and SFTA2 genes. In all, 14 SNPs of VARS2-SFTA2 were analysed among a total of 3902 subjects (1046 cases and 2856 controls). Logistic regression analysis revealed that six SNPs, including the previously reported rs2532932, were significantly associated with the risk of CHB (P = 1.7 × 10(-10) ~0.002). Further linkage disequilibrium and conditional analysis identified two variants (rs9394021 and rs2517459) as new markers of genetic risk factors for CHB rather than the reported SNP from our previous study (rs2532932). To evaluate the cumulative risk for CHB based on all known genetic factors, genetic risk score (GRS) were calculated. As anticipated, the distribution of the number of risk alleles in cases vs. controls clearly differed according to the GRS. Similarly, the odds ratios (ORs) were increased (OR = 0.32-3.97). Our findings show that common variants in the VARS2-SFTA2 gene region are significantly associated with CHB in a Korean population, which may be useful in further understanding genetic susceptibility to CHB.

Loss of nuclear PTEN in HCV-infected human hepatocytes.

BackgroundHepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis and hepatocellular carcinoma (HCC); however, the mechanism of HCV-mediated hepatocarcinogenesis is not well understood. Insufficiency of PTEN tumor suppressor is associated with more aggressive cancers, including HCC. We asked whether viral non-coding RNA could initiate oncogenesis in HCV infected human hepatocytes. The results presented herein suggest that loss of nuclear PTEN in HCV-infected human hepatocytes results from depletion of Transportin-2, which is a direct target of viral non-coding RNA, vmr11.MethodsThe intracellular distribution of PTEN in HCV-infected cells was monitored by immunostaining and Western blots of nuclear and cytoplasmic proteins. Effects of PTEN depletion were examined by comparing expression arrays of uninfected cells with either HCV-infected or vmr11-transfected cells. Target genes suggested by array analyses were validated by Western blot. The influence of nuclear PTEN deficiency on virus production was determined by quantitative analysis of HCV genomic RNA in culture media of infected hepatocytes.ResultsImport of PTEN to the nucleus relies on the interaction of Transportin-2 and PTEN proteins; we show that depletion of Transportin-2 by HCV infection or by the introduction of vmr11 in uninfected cells results in reduced nuclear PTEN. In turn, nuclear PTEN insufficiency correlates with increased virus production and the induction of γ-H2AX, a marker of DNA double-strand breaks and genomic instability.ConclusionAn HCV-derived small non-coding RNA inhibits Transportin-2 and PTEN translocation to the nucleus, suggesting a direct viral role in hepatic oncogenesis.