IL28B Rs12979860 CC Research Articles

IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease

Genetic background may affect liver damage in patients with non-alcoholic fatty liver disease (NAFLD). The main outcomes of the study were to assess whether IL28B rs12979860 and rs8099917 polymorphisms, together with PNPLA3 rs738409 C>G polymorphism, are associated with lobular inflammation and fibrosis, in NAFLD patients. One hundred sixty consecutive NAFLD patients were assessed by liver biopsy (Kleiner score); anthropometric, and biochemical and metabolic features were included. IL28B rs12979860 C>T, IL28B rs8099917 G>C, and PNPLA3 rs738409 C>G single nucleotide polymorphisms were tested. Seventy-four (46.2%) patients had IL28B rs12979860 CC polymorphism, compared with 72 (45%) and 14 (8.8%) with TC and TT variants, respectively. PNPLA3 rs738409 CC polymorphism was present in 47 (29.4%) patients, compared with 79 (49.4%) and 34 (21.3%) with CG and GG variants, respectively. Multivariate logistic regression analysis showed that age (OR 1.043, 95% CI 1.012-1.075, p=0.007), triglycerides (OR 1.005, 95% CI 1.000-1.010, p=0.04), hyperuricemia (OR 5.027, 95% CI 1.839-13.742, p=0.002), IL28B rs12979860 TT/TC (OR 0.219, 95% CI 0.101-0.472, p<0.001), and steatosis grade (OR 1.704, 95% CI 1.048-2.773, p=0.03) were independently linked to moderate-severe lobular inflammation. Finally, IL28B rs12979860 CC was associated with severe fibrosis (F3-F4) on univariate analysis, even if only older age (OR 1.064, 95% CI 1.026-1.104, p=0.001), high HOMA (OR 1.213, 95% CI 1.068-1.377, p=0.003), and lobular inflammation (OR 3.181, 95% CI 1.438-7.036, p=0.004), remained associated in multivariate logistic regression analysis. In NAFLD patients, IL28B rs12979860 CC genotype, together with PNPLA3 rs738409 GG, is associated with the severity of liver damage.

An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C

BackgroundGenetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables.MethodsHALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC).ResultsAmong 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST∶ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study.ConclusionA clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.

Influence of Interleukin-28B Single-Nucleotide Polymorphisms on Progression to Liver Cirrhosis in Human Immunodeficiency Virus–Hepatitis C Virus–Coinfected Patients Receiving Antiretroviral Therapy

Single-nucleotide polymorphisms (SNPs) near the IL28B gene have recently been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in patients with chronic hepatitis C. Because human immunodeficiency virus (HIV) coinfection appears to accelerate HCV-related liver fibrosis progression, any influence of IL28B SNP on the risk of developing cirrhosis might be more easily recognized in the coinfected population. All HIV-HCV-coinfected patients who underwent hepatic elastography before initiating a course of pegylated interferon plus ribavirin therapy at 2 Spanish clinics were retrospectively identified. Liver cirrhosis was defined as >14.5 kPa by transient elastography. The IL28B rs12979860 SNP was examined in a blinded fashion. A total of 304 HIV-HCV-coinfected individuals were analyzed (mean age, 43 years; 80% were male; and 85% were receiving antiretroviral therapy), of whom 18% had cirrhosis. IL28B genotype distribution was as follows: CC, 46%; CT, 43%; and TT, 11%. Cirrhosis was more frequent in CC than CT/TT carriers (24% vs 13%; P = .01). Logistic regression analysis revealed that older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.99-1.12]; P = .08), past alcohol abuse (OR, 1.97; 95% CI, 0.95-4.06; P = .07), and CC IL28B genotype (OR, 2.32; 95% CI, 1.22-4.41; P = .01) were predictors of cirrhosis. Interestingly, mean (SD) alanine aminotransferase (ALT) levels were greater (90 ± 53 vs 71 ± 33 IU/L;, P = .01) in IL28B CC than CT/TT carriers during the prior 4.8 ± 3.8 years. The IL28B rs12979860 CC genotype is associated with a higher prevalence of cirrhosis in HIV-HCV-coinfected patients than CT/TT genotypes, suggesting that IL28B CC carriers may experience a more rapid progression of HCV-related liver fibrosis, perhaps as result of increased liver inflammation. Thus, access to HCV treatment is of utmost importance in IL28B CC carriers, in whom treatment response is better and in whom progression to cirrhosis might occur more rapidly.

IL28B polymorphisms associated with therapy response in Chilean chronic hepatitis C patients

To analyze the association of three IL28B single nucleotide polymorphisms with response to therapy in Chilean patients infected with hepatitis C virus (HCV). We studied two groups of patients with chronic HCV infection (genotype 1), under standard combined treatment with pegylated interferon plus ribavirin. One group consisted of 50 patients with sustained virological response, whereas the second group consisted of 49 null responders. In order to analyze the IL28B single nucleotide polymorphisms rs12979860, rs12980275 and rs8099917, samples were used for polymerase chain reaction amplification, and the genotyping was performed by restriction fragment length polymorphism. The IL28B rs12979860 CC, rs12980275 AA and rs8099917 TT genotypes were much more frequently found in patients with sustained virological response compared to null responders (38%, 44% and 50% vs 2%, 8.2% and 8.2%, respectively). These differences were highly significant in all three cases (P < 0.0001). The three IL28B polymorphisms studied are strongly associated with sustained virological response to therapy in Chilean patients with chronic HCV (genotype 1).

Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection

Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively). We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.

HCV substitutions and IL28B polymorphisms on outcome of peg-interferon plus ribavirin combination therapy

Background and aimsA number of recent studies have shown that human polymorphisms near the IL28B type III interferon (IFNλ) gene influence the response to peg-interferon plus ribavirin combination therapy for...

Observed and Calculated Interleukin-28B Genotype Frequencies in Hepatitis C Virus Infection

There were different rates of viral genotype 3 in the two studies (15.2%1 versus 9.2%2). According to McCarthy et al., patients infected with genotype 3 have the highest rate of the CC genotype. There were differences in the sample sizes of the non-G1–infected groups (66/2761 versus 144/6492). These differences affected the 95% confidence intervals for the rates (54.0%-77.8%1 versus 41.6%-58.4%2). There were differences in the genetic backgrounds of the populations (Spanish versus American Caucasian). In fact, the frequency of CC was also slightly higher among our G1-infected patients (39.1%1 versus 33.5%2). Rates of the IL-28B rs12979860CC genotype among patients infected with G1 HCV or non-G1 HCV in two different studies. In any case, it is important to emphasize that this interesting finding has been reported by independent teams working with two different HCV patient cohorts. Analyzing our non-G1 data with their model, Lindh et al. remarked that “a 67% CC genotype rate … should not develop in an uninfected population with a 45% CC genotype rate … unless the clearance rate in patients carrying a non-CC genotype is higher than that in the CC genotype group.” In our opinion, their model is not entirely appropriate because it does not take into account the different 95% confidence intervals for the rates: the interval for our non-G1 group (54.0%-77.8%) is larger than the interval for our uninfected group (39.6%-49.9%). Lindh et al.'s model suggests a counterintuitive hypothesis similar to that proposed by McCarthy et al., which is based on an interaction model between IL-28B and viral genotypes. This explanation would be unexpected a priori because the IL-28B rs12979860CC genotype and viral genotypes 2 and 3 are good predictors of treatment-induced viral clearance. Moreover, IL-28B rs12979860CC is associated with spontaneous viral clearance, whereas the viral genotype has not been consistently described as a predictor of spontaneous resolution.3 Other explanations for this unexpected overrepresentation of rs12979860CC among non-G1–infected patients, such as epidemiological, virological, and/or immunological factors promoting a positive selection of individuals bearing the rs12979860CC genotype among non-G1–infected patients, are possible. Therefore, further studies in patient cohorts and in vitro assays are needed to test these hypotheses. Marco Antonio Montes-Cano M.D.*, José Raúl García-Lozano M.D.*, Cristina Abad-Molina M.D.*, Manuel Romero-Gómez M.D. , Natalia Barroso M.D. , José Aguilar-Reina M.D. , Antonio Núñez-Roldán M.D.*, María Francisca González-Escribano M.D.*, * Servicio de Inmunología ,Hospital Universitario Virgen del ocío/Instituto de Biomedicina de Sevilla Seville, Spain, Sección Hepatología Hospital Universitario de Valme Seville, Spain, Servicio de Digestivo Hospital Universitario Virgen del Rocío Seville, Spain.