IL28B Rs12979860 Polymorphism Research Articles

Assessment of IL-28: rs12979860 and rs8099917 Polymorphisms in a Cohort of Cuban Chronic HCV Genotype 1b Patients.

Hepatitis C virus (HCV) is a significant global public health problem with >185 million infections worldwide. A series of genome-wide association studies (GWAS) has identified IL-28B polymorphisms as a predictor of sustained virologic response (SVR), as well as spontaneous clearance in chronic HCV genotype 1 patients. The objective of this work was to evaluate the prevalence of IL-28B rs12979860 and rs8099917 polymorphisms in Cuban chronic HCV patients. The study cohort included 73 chronic HCV patients treated with concomitant administration of CIGB-230 and nonpegylated IFN-α plus ribavirin (non-pegIFN-α/R) antiviral therapy. The genotype distribution of IL-28B rs12979860CC, -CT, and -TT was 29, 41, and 30%, respectively, and the distribution for rs8099917TT, -TG, and -GG was 63, 31, and 5%, respectively. The allele frequencies for rs12979860C and -T alleles were 51 and 49%, respectively, and for rs8099917G and -T alleles, the values were 21 and 79%, respectively. SVR rates were 55, 42, and 35% for rs12979860CC, -CT, and -TT, respectively, and 52, 30, and 25% for rs8099917TT, -GT, and -GG, respectively. The combined assessment of both single nucleotide polymorphisms (SNPs) resulted in 3 major genotypes (rs12979860CC/rs8099917TT, rs12979860CT/rs8099917TT, and rs12979860CT/rs8099917GG) with a frequency of 30.1, 21.9, and 20.5%, respectively. In patients with heterozygous variant rs12979860CT, the additional genotyping of rs8099917 contributed to increase the SVR rate. It is concluded that in Cuban HCV-infected patients, the responder homogeneous variant rs8099917TT is the most frequent genotype. The simultaneous genotyping of 2 IL-28B SNPs could improve the prediction of SVR contributing to better therapeutic decisions and treatment management.

The Effect of IL28B Gene Polymorphism on Treatment Response in Iranian Patients with Hepatitis C Virus Infection

Background: The hepatitis C virus (HCV) is an important human pathogen affecting an estimated 120 - 170 million individuals in the world. Polymorphisms of the IL28B gene are strongly associated with sustained virological response in patients with chronic hepatitis C treated with peginterferon and ribavirin. Objectives: The aims of this study were to compare the allelic and genotypic frequencies of the IL28B rs12979860 polymorphism in sustained virological response in patients who did not respond to the standard of care treatment and to verify whether there is a correlation between the viral load and the IL28B rs12979860 polymorphism. Methods: This cross-sectional study was carried out on 75 HCV-infected patients, including 45 responders to treatment (group 1) and 30 nonresponders (group 2). We compared the allele and genotype frequencies of the IL28B rs12979860 between the two groups using the PCR-RFLP method. Results: The genotype frequencies of rs12979860 polymorphism in group 1 were CC (28.9%), CT (37.8%) and TT (33.3%) and in group 2 were CC (6.7%), CT (43.3%) and TT (50%). There was a significant difference in genotype frequencies of IL28B polymorphism between the two groups (P = 0.03). There was no significant association between the viral load and IL28B rs12979860 genotypes in either group 1 (P = 0.3) or group 2 (P = 0.2). Conclusions: Our findings indicate that patients with the homozygous CC genotype in the IL28B gene had a significantly higher rate of response to treatment than those with the TT or CT genotypes. Nor does the IL28B rs12979860 polymorphism affect the viral load.

Non Favorable Genotype is Predominant at IL28B RS12979860 Polymorphism in Hepatitis B Related Hepatocellular Carcinoma

Background and Aim: The highest incidence of HCC is in Asia, accounting for about 76% of all cases worldwide. In South East Asia, hepatitis B is the most common underlying cause. Although numerous associations between environmental factors (e.g. cigarette smoking, heavy alcohol drinking, male gender, older age), viral factors (e.g. viral load, active replication, genotype, core promoter mutations) and the development of HCC in chronic HBV infection have been identified, a clear understanding of the role of host genetics remains illusive. Bangladesh is a densely populated country with about 160 million populations, where HBsAg positivity in the healthy population is 5.4%. The aim is to evaluate the role of host IL28B (interleukin 28B; interferon lambda 3) single nucleotide polymorphism (SNP) in predicting hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) susceptibility. Methods: Single SNP in the IL28B gene (rs12979860C/T) were examined in 116 subjects (including 44 HBV-related HCC patients, 42 non-HCC patients with chronic hepatitis B and 30 healthy controls). The study was done at the Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from January 2012 to December 2013. The polymorphism of IL28B rs12979860 was analyzed by a genotyping technique, based on polymerase chain reaction (PCR) followed by restriction enzyme analysis at the Department of Microbiology & Immunology, BSMMU. Results: The frequency of CC homozygosity was 70% in healthy controls and 45.5% in HCC, the difference being statistically significant (χ2 = 4.35, P = 0.03). Statistically significant difference was also seen between non-HCC patients with chronic hepatitis B (CHB) (69%) and HCC (45.5%) (χ2 = 4.35, P = 0.03). However, this significant finding was not seen between non-HCC patients with chronic hepatitis B (CHB) and healthy controls. Carriers of the minor T allele in rs12979860 had a higher risk of HCC compared with non-carriers (χ2 = 4.78, P = 0.02). Conclusion: Our results suggest that, T allele and non-CC genotypes have strong predictive effect of developing HCC and IL28Brs 12979860C/T polymorphism might influence susceptibility to HCC. The author has none to declare.

Early reduced liver graft survival in hepatitis C recipients identified by two combined genetic markers

HLA and IL-28B genes were independently associated with severity of HCV-related liver disease. We investigated the effects of these combined genetic factors on post-transplant survival in HCV-infected recipients, aiming to provide new data to define the optimal timing of novel antiviral therapies in the transplant setting. HLA-A/B/DRB1 alleles and IL-28B rs12979860 (C > T) polymorphism frequencies were determined in 449 HCV viremic recipients and in their donors. Median follow-up was 10 years; study outcome was graft survival. HLA-DRB1*11 phenotype and IL-28B C/C genotype were significantly less frequent in recipients than donors (27.8% vs. 45.9% and 27.4% vs. 44.9%, respectively, P < 0.00001). Ten-year graft survival was better in patients with HLA-DRB1*11 (P = 0.0183) or IL-28B C/C (P = 0.0436). Conversely, concomitant absence of HLA-DRB1*11 and IL-28B C/C in 228 (50.8%) predicted worse survival (P = 0.0006), which was already evident at the first post-transplant year (P = 0.0370). In multivariable Cox analysis, absence of both markers ranked second as risk factor for survival (HR = 1.74), following donor age ≥ 70 years (HR = 1.77). In the current era of direct-acting antiviral agents, the negative effects of this common immunogenetic profile in HCV-infected recipients could be most effectively neutralized by peri-transplant treatment. This should be particularly relevant in countries where elderly donors represent an unavoidable resource.

Effect of IL-28B polymorphisms on the natural course of HBV infection

The prediction of the consequences of disease is important to determine the therapy approaches and prevention of the chronical state in patients infected with hepatitis B virus (HBV). In recent years various studies are carried on to investigate the effect of IL-28B gene polymorphisms on the clinical course or therapy response in patients with chronic hepatitis B infection. The aim of the study was to evaluate the influence of IL-28B rs12979860 polymorphisms on the natural course of HBV infection. The study was designed prospectively, and the subjects were randomly selected among patients admitted to infectious disease outpatient clinics of Kocatepe University Medical School Hospital and Yunus Emre State Hospital located at provinces in Central Anatolia, Turkey. A total of 99 cases were included in the study and evaluated into three groups, namely, chronic hepatitis B patients (group 1, n= 43); inactive HBV carriers (group 2, n= 34) and subjects with acquired immunity after native infection (group 3, n= 22). There were no significant differences regarding the age and gender distribution between the groups (p> 0.05). All subjects were investigated for the IL-28B promoter single nucleotide polymorphism rs12979860 at position 3176 C/T, by real-time polymerase chain reaction (RT-PCR). Evaluation of the range of IL-28B rs12979860 C/T polymorphisms observed in the study groups showed that, the frequency of CC, CT and TT allels were as follows; 34.9%, 48.8% and 16.3 % in group 1; 47.1%, 35.3% and 17.6% in group 2; 63.6%, 27.7% and 13.6% in group 3, respectively. No significant differences were observed between the groups in terms of C/T allel distriubution (p> 0.05). However, in spite of statistical insignificance, the rate of CC allel in IL-28B rs12979860 gene was the highest in immune subjects (63.6%), while it was the lowest in chronic hepatitis B patients (34.9%). According to our data, IL-28B rs12979860 gene polymorphisms were not effective on the clinical course of HBV infection. In conclusion, further studies with large numbers of patients are needed to support these data.

Distribution of IL-28B genotypes in patients with hepatitis C and healthy individuals in Jahrom city.

The purpose of this study was to compare the distribution of interleukin (IL)-28B genotypes between Iranian healthy individuals and patients with chronic hepatitis C based on the genotype. Polymorphisms in the region of IL-28B gene have been identified as the strongest genetic pretreatment predictor of sustained virological response (SVR) in hepatitis C infection. In this study, 147 patients with chronic hepatitis C and 80 healthy individuals were included. The IL-28B rs12979860 and rs8099917 polymorphisms were genotyped by PCR-RFLP method and the frequency of IL-28B polymorphisms with respect to HCV genotypes was also determined. The frequencies of rs12979860 TT, CC and CT genotypes in the chronic hepatitis C patients and healthy individuals were as follows: 10.8% vs. 11.3%, 38.7% vs. 46.2% and 50.3% vs. 42.5%. Also, the frequencies of rs8099917 TT, GG and GT genotypes in the chronic hepatitis C patients was 61.9%, 6.1% and 32% and in controls was 47.5%, 11.2% and 41.3%. The differences in the distribution of rs12979860 genotypes and alleles between HCV genotype 1 and HCV genotype 3a infected patients were statistically significant. The rs12979860 C allele is the favorable allele for the spontaneous clearance of HCV. It seems that the impact of IL-28B polymorphism on the spontaneous clearance of HCV genotype 3 is more prominent than HCV genotype 1, which results in the observation of higher rs12979860 C allele frequency in chronic hepatitis C patients with HCV genotype 3 than HCV genotype 1.

Association between CXCL10 and DPP4 Gene Polymorphisms and a Complementary Role for Unfavorable IL28B Genotype in Prediction of Treatment Response in Thai Patients with Chronic Hepatitis C Virus Infection.

Pretreatment serum levels of interferon-γ-inducible protein-10 (IP-10, CXCL10) and dipeptidyl peptidase-4 (DPP IV) predict treatment response in chronic hepatitis C (CHC). The association between functional genetic polymorphisms of CXCL10 and DPP4 and treatment outcome has not previously been studied. This study aimed to determine the association between genetic variations of CXCL10 and DPP4 and the outcome of treatment with pegylated interferon-α (PEG-IFN-α) based therapy in Thai patients with CHC. 602 Thai patients with CHC treated using a PEG-IFN-α based regimen were genotyped for CXCL10 rs56061981 G>A and IL28B rs12979860 C>T. In addition, in patients infected with CHC genotype 1, DPP4 (rs13015258 A>C, rs17848916 T>C, rs41268649 G>A, and rs 17574 T>C) were genotyped. Correlations between single nucleotide polymorphisms, genotype, and treatment response were analyzed. The rate of sustained virologic response (SVR) was higher for the CC genotype of IL28B rs12979860 polymorphisms than for non-CC in both genotype 1 (60.6% vs. 29.4%, P < 0.001) and non-genotype 1 (69.4% vs. 49.1%, P < 0.05) CHC. SVR was not associated with the CXCL10 gene variant in all viral genotypes or DPP4 gene polymorphisms in viral genotype1. Multivariate analysis revealed IL28B rs12979860 CC genotype (OR = 3.12; 95% CI, 1.72–5.67; P < 0.001), hepatitis C virus RNA < 400,000 IU/ml (OR = 2.21; 95% CI, 1.22–3.99, P < 0.05), age < 45 years (OR = 2.03; 95% CI, 1.11–3.68; P < 0.05), and liver fibrosis stage 0–1 (OR = 1.64; 95% CI, 1.01–2.65, P < 0.05) were independent factors for SVR. Unfavorable IL28B rs12979860 CT or TT genotypes with the CXCL10 rs56061981 non-GG genotype were associated with a higher SVR than GG genotype (66.7% vs. 33.0%, P = 0.004) in viral genotype 1. In Thai CHC genotype 1 infected patients with an unfavorable IL28B rs12979860 CT/TT genotype, the complementary CXCL10 polymorphism strongly enhances prediction of treatment response.

The complete title: The effect of interleukin-28B rs12979860 polymorphism on the therapeutic response of Moroccan patients with chronic hepatitis C

Background/aimsThere is increasing evidence for the effect of rs12979860 IL28B polymorphism in response to the standard treatment PEG-IFN/RBV (i.e. combination of pegylated interferon and ribavirin) in chronic hepatitis C virus (HCV) infection. The present study aimed to determine the impact of IL28B associations in interferon responsiveness in 187 Moroccan patients with chronic HCV infection. MethodsHCV RNA levels were measured with a real-time RT-PCR assay and treatment efficacy was assessed by sustained virological response (SVR) and patients were classified as responders or non-responders. IL28B rs12979860 polymorphism genotyping was achieved by PCR-HRM technique. ResultsThe results demonstrated that SVR was achieved in 102 patients (55%); while 69 were non-responders (37%) and 16 relapsed (8%). Genotype 1 was the predominant HCV genotype detected in 112 patients followed by genotype 2 in 56 patients. The genotype CC was observed in 42 cases (25%); CT in 69 (41%) and TT in 57 (34%) demonstrating a C allele frequency of 46%. The SVR was observed in 32 patients with genotype CC accounting for 76%. The frequencies of rs12979860 CC type in infected individuals with HCV genotype 1 were 47% and 12% respectively in SVR and non-SVR groups. A highly statistically significant association between this SNP and SVR was found (p<0.001). Using multivariate logistic regression analysis, CC genotype was an independent factor for SVR. In the group of patients infected with genotype 2, SVR rate was 79%. The frequency of rs12979860 CC type in SVR group (n=4) was 9% and rs12979860 non-CC genotype was highly associated with SVR (p=0.001). ConclusionThis finding adds evidence that genotyping for the IL-28B rs12979860 SNP can be a good parameter for the prediction of treatment success in patients with chronic hepatitis C before initiation of antiviral therapy in Morocco.

IL28B rs12980275 polymorphism shows association with response to treatment in Pakistani patients with chronic hepatitis C.

The aim of this study was to describe the genetic characteristics of Pakistani patients infected with hepatitis C virus (HCV) in relation to IL28B polymorphisms and its association to interferon and ribavirin treatment response. A total of 220 patients, infected with HCV were enrolled, out of which 100 were responders and 120 were nonresponders. The whole blood samples were collected to extract viral RNA and genomic DNA. PCR following the restriction fragment length polymorphism method was used to genotype IL28B rs12979860, rs8099917, and rs12980275 polymorphisms. Liver biopsies and HCV genotyping were performed in nonresponder patients. The rs12980275 AA genotype exhibited significant correlation to treatment response and was found in 62% of the responders and 37.5% of nonresponder patients, whereas AG genotype was noticed frequently in the nonresponder group (P < 0.0001). The rs12979860 CT and rs8099917 TT genotypes were found in 74% and 66% of the responders as compared to 58.3% and 50.8% in nonresponder patients (P = 0.001 and P = 0.032) respectively. HCV 3a genotypes were detected in 50.8% of the nonresponder patients. No significant association was detected between liver biopsy findings and IL28B SNPs (P > 0.05). The results showed the significant association of rs12980275 polymorphism with treatment response in HCV patients followed by rs12979860 and rs8099917. This is the first report describing the association of rs12980275 with response to HCV treatment from Pakistan. These findings may help in predicting the outcome of pegylated interferon and ribavirin treatment in HCV patients, and may reduce the side effects and cost of treatment in predicting non-responder patients.

Programmed Cell Death-1 Polymorphism rs11568821 is a predictor of Treatment Outcome in Chronic HCV Genotype 4 Infection

Background & Aim: Recently, a single nucleotide polymorphism of Programmed Cell Death-1 (PD-1) gene has been reported to be associated with sustained virologic response (SVR) and to increase the predictive value of IL28B/CC genotype in chronic hepatitis C virus (HCV) genotype 1 and 3 infections. However, to date, there is no data concerning genotype 4. The aim of this study was to investigate the effect of PD-1.3 polymorphism on treatment outcome in patients with chronic HCV-4 infection. Methods: 200 HCV-4 chronic infected patients were recruited and received PEG- IFN-α and ribavirin therapy. They were classified according to their response to treatment into SVR and Non-responders (NR) groups. PD-1.3 and IL28B rs12979860 polymorphisms were genotyped by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) analysis. Results: PD-1.3/GG genotype was over-represented in NR (79.8%) than in SVR patients (58.3%), P=0.001. PD-1.3/A allele was associated with SVR (P <0.001). IL28B/CC genotype was recognized in 60.4% of SVR vs. 25.9% of NR patients (P <0.001). The unfavorable TT genotype was revealed in 4.2% of SVR vs. 23.1% of NRs (P<0.001). Using logistic regression analysis, IL28B/CC genotype showed a predictive value of 58% which increased to 62.8% in the presence of PD1.3/AA genotype. Conclusions: PD-1.3 polymorphism is a new predictor of treatment outcome in chronic HCV genotype 4 infected patients and allele a associates with SVR. Genotyping of both IL28B rs12979860 and PD-1.3 is valuable in these patients for early prediction of the response to combined interferon and ribavirin therapy.

CC Genotype at rs12979860 of IL28B Is Associated With Lower Risk of New-onset Diabetes After Transplantation in Adult Patients With Liver Transplantation for Hepatitis C Cirrhosis

IntroductionNew-onset diabetes mellitus after transplantation (NODAT) in patients undergoing liver transplantation (LT) for hepatitis C virus (HCV)-related cirrhosis is associated with more aggressive HCV recurrence on the graft, rapid progression of fibrosis, and lower rate of sustained viral response to antiviral therapy. The CC genotype at rs12979860 of the IL28B is associated with greater rates of spontaneous clearance of HCV and response to antiviral therapy. IL28B acts on the interferon-stimulated genes through the JAK-STAT pathway, which is related to the development of insulin resistance. The aim of this study was to investigate whether IL28B rs12979860 polymorphism is associated with the development of NODAT after LT for cirrhosis owing to HCV infection. MethodsWe analyzed 99 patients (age, 52.7 ± 9.4 years; 70% male) who underwent LT for HCV-related cirrhosis, with ≥1 year of follow-up and with available DNA sample. NODAT was defined starting from the sixth month after LT, according to the international consensus guidelines. Genotyping was carried out by real-time polymerase chain reaction and analysis of the melting temperature with the LightCycler 480 system. ResultsTwenty-eight patients (28.3%) developed NODAT. CC genotype at rs12979860 of IL28B was associated with a lesser incidence of NODAT versus non-CC genotypes (P = .05; odds ratio, 0.31; 95% CI, 0.11–0.92). We did not find any association between NODAT and age at transplantation, gender, pretransplant body mass index, presence of hepatocellular carcinoma, type of initial immunosuppression (cyclosporine, tacrolimus or corticosteroids) or acute rejection treated with steroids. ConclusionThe CC genotype at rs12979860 of IL28B is a protective factor for NODAT in patients with LT for HCV-related cirrhosis.

IL28B rs12979860 gene polymorphism in Egyptian patients with chronic liver disease infected with HCV.

Egypt has one of the highest prevalences of hepatitis C virus (HCV) infection worldwide. Although the IL28B gene polymorphism has been shown to modify the course of chronic HCV infection, this has not been properly assessed in the Egyptian population. The IL28B rs12979860 single nucleotide polymorphism (SNP) was therefore examined in 256 HCV-infected Egyptian patients (group II) at different stages of disease progression and in 48 healthy volunteers (group I). Group II was subdivided into GII-A (chronic hepatitis patients, n=119), GII-B (post hepatitis cirrhosis, n=66) and GII-C (HCC on top of cirrhosis, n=71). The C/T genotype was the commonest in all groups. It was more frequent in GI (52%) than in GII (48%). There was no significant difference in the frequency of C/T and C/C or T/T genotypes between groups and subgroups (p=0.82). Within the subgroups; the C/C genotype was more common in GII-B while C/T and T/T genotypes were more common in GII-C, though with no significant difference (p=0.59 and p=0.80). There was no significant association between IL28B rs12979860 SNP and viral load, ALT, AFP level, METAVIR scores for necro-inflammation and fibrosis, and Child-Pugh classification. 1) IL28Brs12979860 C/T genotype is the commonest genotype in HCV-associated CH and HCC in Egypt. 2) IL28Brs12979860 polymorphisms are not associated with disease progression or aggression (histological staging, severity of fibrosis in CH or the incidence of post-HCV HCC). 3) Differences in IL28Brs12979860 genotypes could be a consequence of environmental or ethnic variation.

Chronic hepatitis B and IL28B rs12979860 polymorphism: preliminary study

The aim of this study is to evaluate the role of IL28B rs12979860 polymorphism on pegylated interferon (peg IFN) and oral antiviral treatment in chronic hepatitis B (CHB) patients and to investigate the relationship between the severities of illness with this polymorphism. 74 CHB patients who are received treatment, 61 asymptomatic carriers and 40 healthy controls were recruited in this study. Genomic DNA of controls and patients were extracted from whole blood using High Pure PCR Template Preparation Kit (Roche, Mannheim, Germany) according to the manufacturer's instructions and stored at 4 °C. Genotype distribution of the IL-28B polymorphism at position -3176C/T (rs12979860) (LightMix Kit IL28B, Cat.-No. 40-0588-32 TIB MOLBIOL, Berlin, Germany) was detected by real time PCR (Roche Diagnostics, Manheim, Germany). Thirty of the patients with CHB received peg IFN-α treatment. There were no significant difference between groups by means of age, gender and IL28B rs12979860 polymorphism (p = 0.122, p = 0.07, p = 0.376 respectively). Patients with chronic hepatitis were categorized as grade and stage (minimal, moderate and severe) and then were analyzed for the polymorphism. There was no effect of IL28B -3176 C/T polymorphism on severity of illness (p = 0.293 for grade, p = 0.911 for stage). When the CHB treatment monitored in different time arrivals (beginning, 3th, 6th and 12th months of the treatment) in order to see if there was an effect on virological and biological response none of the genotypes of IL28B -3176C/T polymorphism altered peg IFN or oral antiviral treatment process. There are conflicting results about the role of IL28B rs12979860 polymorphism in CHB in the literature. In this preliminary study, we observed that IL28B rs12979860 polymorphism was not related with severity of illness and also was not effective on treatment response.

Investigation of PNPLA3 and IL28B Genotypes on Diabetes and Obesity After Liver Transplantation: Insight Into Mechanisms of Disease

To identify genetic risks for obesity and diabetes postliver transplantation (LT), LT recipients underwent genotyping for IL28B rs12979860 (n = 295) and PNPLA3 rs738409 (n = 205) polymorphism in both donors and recipients. The development of obesity and diabetes/impaired fasting glucose (IFG) was determined 1–5 years post-LT. Recipient PNPLA-3 genotype was independently associated with obesity (BMI > 30) at 3 years posttransplant (genotype CC 33.7%, CG 48.3% and GG 82.4%, p = 0.002), with an odds ratio (OR 2.54, CI 1.38–4.66, p = 0.003), associated with the G allele. Diabetes/IFG diagnosed within 5 years posttransplant associated with PNPLA-3 non-CC genotype (HR 1.59, 1.12–2.26, p = 0.010), but not IL28B TT genotype (HR 1.46, 0.94–2.27, p = 0.092). No genotype variable was independently predictive of diabetes/IFG. The combination of PNPLA-3 non-CC and IL28B TT genotype was associated with increased risk of diabetes/IFG compared to PNPLA-3 CC, IL28B non-TT (HR 2.64, CI 1.30–5.39, p = 0.008). Donor genotypes were not associated with any of the outcomes analyzed. In conclusion, PNPLA-3 non-CC genotype is associated with posttransplant obesity but not independently with diabetes/IFG. The lack of donor related risk suggests a peripheral rather than central mechanism of insulin resistance in liver transplant recipients.

IL28B CC genotype: a protective factor and predictor of the response to interferon treatment in chronic hepatitis C virus infection

In chronic hepatitis C-virus infection the possible role of gene variants encoding cytokines has become the focus of interest. The aim of the study was to investigate the effect of IL28B polymorphisms on the outcome of chronic hepatitis C-virus genotype 1 infection in the Hungarian population. In addition, the association between IL28B genotypes and the Th1/Th2 cytokine production of activated peripheral blood monocytes and lymphocytes was evaluated. Total of 748 chronic hepatitis C-virus genotype 1 positive patients (365 males and 383 females, aged between 18 and 82 years; mean age, 54±10 years) were enrolled, of which 420 patients were treated with pegylated interferon plus ribavirin for 24-72 weeks. Of the 420 patients, 195 patients (46.4%) achieved sustained virological response. The IL28B rs12979860 polymorphism was determined using Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA). For cytokine studies, tumour necrosis factor-α, interleukin-2, interferon-γ, interleukin-2 and interleukin-4 production by LPS-stimulated monocytes and PMA-ionomycine activated lymphocytes were measured from the supernatant of the cells obtained from 40 hepatitis C-virus infected patients, using FACS-CBA Becton Dickinson test. The cytokine levels were compared in patients with different (CC, CT, TT) IL28B genotypes. The IL28B rs12979860 CC genotype occurred in lower frequency in hepatitis C-virus infected patients than in healthy controls (26.1% vs 51.4%, OR 0.333, p<0.001). Patients carried the T allele with higher frequency than controls (73.9%, vs 48.6%, OR 3.003, p<0.001). Pegylated interferon plus ribavirin treated patients with the IL28B CC genotype achieved higher sustained virological response rate than those with the CT genotype (58.6% vs 40.8%, OR 2.057, p = 0.002), and those who carried the T allele (41.8%, OR1.976, p = 0.002). LPS-induced TLR-4 activation of monocytes resulted in higher tumour necrosis factor-α production in patients with the IL28B CC genotype compared to non-CC individuals (p<0.01). Similarly, increased tumour necrosis factor-α, interleukin-2 and interferon-γ production by lymphocytes was found in the IL28B CC carriers (p<0.01) CONCLUSIONS: The IL28B CC genotype exerts protective effect against chronic hepatitis C-virus infection and may be a pretreatment predictor of sustained virological response during interferon-based antiviral therapy. The IL28B CC polymorphism is associated with increased Th1 cytokine production of activated peripheral blood monocytes and lymphocytes, which may play a role in interferon-induced rapid immune control and sustained virological response of pegylated interferon plus ribavirin treated patients.

Clinico‐pathological significance of hepatitis C virus core antigen levels in chronic infection

Hepatitis C virus core antigen (HCVcoreAg) may be measured in serum with a sensitive, recently validated assay. Beyond its value as a marker of viral infection, there are little data on its relation with clinical, histological, and virological parameters. In this study, the significance of HCVcoreAg levels was studied in a prospective cohort of 114 patients with chronic hepatitis C. HCVcoreAg was measured by a commercial chemiluminescent microparticle immunoassay. Clinical and virological data included quantitative HCV-RNA, HCV genotype, ALT, GGT, IL28B rs12979860 polymorphism as well as liver histology parameters. HCVcoreAg levels were correlated significantly with HCV-RNA (r=0.56; P<0.0001) but also with ALT levels (r=0.258; P<0.01) and liver necroinflammatory activity (r=0.205; P<0.04). Patients harbouring HCV genotype 3 showed lower levels of HCVcoreAg than both genotype 1 and two patients. In genotype 3, a direct correlation between steatosis and HCVcoreAg was found. Levels of HCVcoreAg also varied according to the IL28B genotype. These data suggest that the evaluation of HCVcoreAg serum levels may provide relevant data for the baseline clinical evaluation of chronic hepatitis C patients. HCVcoreAg serum levels may be a useful tool to further the understanding of chronic hepatitis C pathobiology.

Genotype 3 and Favorable IL28B Polymorphism as Predictors of Good Response for Hepatitis C Recurrence Post Liver Transplantation

Background: Treatment of hepatitis C after liver transplantation is associated with poor sustained virological response (SVR) in genotype 1 patients. Data is sparse about genotype 3 and role of IL28B rs12979860 polymorphism in post transplant setting.

Impact of IL-28B polymorphisms on pegylated interferon plus ribavirin treatment response in children and adolescents infected with HCV genotypes 1 and 4

IL-28B polymorphisms are predictors of response to therapy in adults infected with hepatitis C. We do not know whether they are markers of response to therapy in children and adolescents. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the IL-28B gene could influence the probability of response to therapy compared with other known baseline prognostic factors and correlate with clinical findings in pediatric patients infected with hepatitis C virus (HCV) genotypes 1 or 4. We determined three SNPs of IL-28B (rs12979860, rs12980275, and rs8099917) in 82 patients with chronic HCV infection treated with pegylated interferon alpha and ribavirin (peg-IFNα/RBV). Treatment response and clinical data were analyzed. Overall, sustained virological response (SVR) was achieved by 45 % of patients infected with difficult-to-treat HCV genotypes 1 and 4. Except for IL-28B polymorphisms, there was no association of SVR with any other clinical data. IL-28B rs12979860 CC [odds ratio (OR), 6.81; p = 0.001] and rs8099917 TT (OR, 3.14; p = 0.013) genotypes were associated with higher SVR rates. IL-28B rs12980275 was not significantly associated with SVR (p = 0.058). Only the distribution between CC and CT–TT genotypes of rs12979860 significantly differentiated patients achieving early virological response (EVR) (OR, 10.0; p = 0.011). Children with the rs12979860 CC genotype had significantly higher baseline viral load compared with CT–TT patients (p = 0.010). In children and adolescents chronically infected with HCV genotypes 1 and 4, IL-28B rs12979860 and rs8099917 polymorphisms were the only predictors of response to peg-IFN/RBV.

Distribution of IL28B Genotypes in Iranian Patients with Chronic Hepatitis C and Healthy Individuals

BackgroundIL28B polymorphism is recognized as one of the most prominent predictors of hepatitis C spontaneous and treatment-induced clearance. Interestingly, the favorable genotypes of IL28B are found to be more frequent in Asian ethnicity than Caucasian and African populations, respectively. A few studies reported that there is a mysterious association between the IL28B polymorphism and the hepatitis C virus (HCV) genotype in patients with chronic hepatitis C but they did not give any reason for this phenomenon.ObjectivesThe foremost purpose of this study was to compare the distribution of IL28B genotypes between Iranian healthy individuals and patients with chronic hepatitis C.Patients and MethodsIn this study, 921 patients with chronic hepatitis C and 142 healthy individuals were included. The IL28B rs12979860 and rs8099917 polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.ResultsThe frequency of IL28B rs12979860 CC, CT, and TT genotypes in chronic hepatitis C patients was 38%, 48.8%, and 13.2% and in healthy individuals was 43.7%, 48.6%, and 7.7%. Also, the frequency of IL28B rs8099917 TT, GT, and GG genotypes in chronic hepatitis C patients was 58.3%, 37.1%, and 4.6% and in healthy individuals was 64.1%, 32.4% and 3.5%. The differences in the distribution of IL28B rs12979860 and rs8099917 genotypes between patients with chronic hepatitis C and healthy individuals were not statistically significant. When we compared the distribution of IL28B genotypes between the healthy group and the HCV infected patients by HCV genotype, we found 9.8% higher frequency of rs12979860 CC genotype in the healthy individuals than HCV genotype 1 infected patients (P = 0.03) however there was no significant difference in the distribution of rs12979860 genotypes between the healthy and HCV genotype 3 infected groups (P = 0.46).ConclusionsIt seems that the impact of IL28B polymorphism on the spontaneous clearance of HCV genotype 1 is more prominent than HCV genotype 3 which results in the observation of higher rs12979860 C allele frequency in chronic hepatitis C patients with HCV genotype 3 than HCV genotype 1.

Insulin resistance predicts sustained virological response to treatment of chronic hepatitis C independently of the IL28b rs12979860 polymorphism

Insulin resistance has been strongly associated with the attainment of sustained viral response (SVR) in hepatitis C patients. To determine, in a cohort of Spanish patients with chronic hepatitis C treated with peginterferon plus ribavirin (P+R), whether insulin resistance predicts SVR independently of interleukin-28B rs12979860 polymorphism. Insulin resistance was measured as [HOMA-IR = Insulin (IU/mL)*glucose (mmol/L)/22.5]. Genotype, viral load and histological fibrosis using Scheuer score were also measured. Binary logistic regression analysis was used for statistical purposes. In a cohort of 240 patients [78% genotype 1, 24% showing advanced fibrosis, 71% high viral load (≥800 000 IU/mL), 31% IL28b genotype CC and 50% with HOMA >2] treated with P+R, 126 (53%) reached SVR. HOMA-IR index (HOMA <2: 63% vs. HOMA >2: 42%; P = 0.001 and IL28b (genotype CC: 68% vs. genotype CT/TT: 45%; P = 0.002) were significantly associated with SVR. In multivariable logistic regression analysis in the overall cohort, variables independently associated were: viral genotype OR: 0.29 (95% CI: 0.11-0.78), P = 0.01; fibrosis OR: 1.62 (95% CI: 1.22-2.16), P = 0.001; HOMA-IR OR: 1.22 (95% CI: 1.02-1.47), P = 0.03; and IL28B genotype OR: 2.43 (95% CI: 1.45-4.07), P = 0.001. The analyses also showed that degree of steatosis, HOMA-IR >2, mild fibrosis and IL28B CC genotype were significantly related to SVR in patients infected with HCV genotypes 1&4, but not in those with genotypes 2&3. No differences were seen in glucose, insulin level or HOMA-IR index segregated according to IL28B genotypes. Our results suggest that insulin resistance, fibrosis stage and IL28B polymorphisms were independent variables associated with sustained viral response.