Variation In IL28B Research Articles

The Impact of IL28B Gene Polymorphisms on Drug Responses

The Impact of IL28B Gene Polymorphisms on Drug Responses

Genetic variation in IL28B (IFNL3) and response to interferon-alpha treatment in myeloproliferative neoplasms.

In myeloproliferative neoplasms (MPN), interferon-alpha (IFN-α) is an effective treatment with disease-modifying properties but currently with no clear predictors of treatment outcome. Recent genomewide association studies in chronic hepatitis C have found a strong influence of genetic polymorphism near the IL28B (IFNL3) gene in response to IFN-α treatment. In this study, we sought to evaluate the prognostic impact of IL28B rs12979860, rs8099917, and rs12980275 on IFN-α treatment response in myeloproliferative neoplasms. We retrospectively evaluated 100 patients with MPN treated with IFN-α. The hematologic treatment response on IFN-α was compared between patients and correlated with host genetic variations in IL28B. The genotypes of IL28B were determined by allelic discrimination assays. The CC genotype of rs12979860 was found significantly associated with hematologic response in polycythemia vera (PV) with a complete response (CR) in 79% (CC) compared to 48% (non-CC), (P=.036). No association between the genotypes and treatment response on hydroxyurea was found. These results imply an effect of IL28B genotype on the outcome of IFN-α treatment in MPN.

The birth and potential death of IL28B genotyping for hepatitis C therapy.

The birth and potential death of IL28B genotyping for hepatitis C therapy.

Association of IL28B polymorphisms with peginterferon treatment response in Chinese Han patients with HBeAg‐positive chronic hepatitis B

To investigate whether IL28B polymorphisms could affect the treatment response to peginterferon alpha (PEG-IFN) in chronic hepatitis B (CHB) patients in the Chinese Han population. A total of 212 hepatitis B e antigen (HBeAg)-positive patients treated with PEG-IFN monotherapy were enrolled in this study. Genotype analysis was performed for IL28B rs12980275, rs12979860 and rs8099917 using the MassArray system. Response was defined as cases showing normal aminotransferase (ALT) levels, HBV DNA level < 200 IU/ml and HBeAg seroconversion after 48 weeks of PEG-IFN therapy. The patients were infected with hepatitis B virus (HBV) genotype B (44.8%) and C (55.2%) with a total response rate of 34.9%. For the three SNPs, there were significant differences between the response (R) and non-response (NR) groups both in allele frequencies and genotype distributions. IL28B genotype was independently associated with R for AA vs. N-AA (OR 2.70, 95% CL 1.21-6.01; P = 0.015) at rs12980275 after adjustment for sex, age, HBV genotype, baseline levels of HBV DNA and ALT. There were similar results for rs12979860 CC vs. N-CC (OR 2.56, 95% CL 1.15-5.67; P = 0.021) and rs8099917 TT vs. N-TT (OR 2.80, 95% CL 1.23-6.39; P = 0.015) respectively. Furthermore, one block formed by rs12980275 and rs12979860 was identified in this study. In multivariate analyses, the most common haplotype A-C was independently associated with high rates of R (OR 2.53, 95% CL 1.20-5.34; P = 0.015). Our study suggested that genetic variations in IL28B may play a critical role in PEG-IFN efficacy in HBeAg-positive CHB patients in Han Chinese.

110 : Characterization of the newly identified interferon Lambda 4

In 2009 genome-wide association studies identified the rs12979860 and rs8099917 SNPs on chromosome 19q13.13 near the interferon lambda ( IFN-λ3 ) gene as variants associated with both spontaneous Hepatitis C virus (HCV) clearance and response to pegIFN- α /RBV treatment [1,2]. Recently a dinucleotide variant, denoted ss469415590 (TT > DG) was discovered upstream of IFN-λ3 . The DG variant leads to a new open reading frame encoding a new member of the type III interferon family, IFN-λ4 , [3] It seems that ss469415590 has a stronger correlation with a positive outcome of pegIFN- α /RBV treatment than rs12979860 and rs8099917. Studies have found that individuals with chronic hepatitis C who express IFN- λ 4 before treatment have higher hepatic expression of ISGs but poorer ISG response to pegIFN- α /RBV treatment. Like the other members of the type III interferon family IFN- λ 4 induces STAT1 and STAT2 phosphorylation, and activate the transcription of ISGs. The exact signaling receptor of IFN- λ 4 has not been identified but based on the protein sequence it is expected to signal via IFN- λ R1. Whether it also uses IL-10R2 like the other type III interferons remains to be determined. Likewise the correlation between IFN- λ 4 expression and HCV is still not understood. IFN- λ 4 seems to be poorly exported from human cells possibly because of a very week signal peptide. We have produced, refolded and purified recombinant IFN- λ 4 in Escherichia coli . The protein is capable of inducing ISGs and has antiviral activity comparable to IFN- λ 3. Using this protein we have investigated the receptor complex utilized by IFN- λ 4. We have furthermore explored the importance of the signal peptide for the poor export of IFN- λ 4 from human cells. 1. Ge, D., et al., Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance . Nature, 2009. 461 (7262): p. 399–401, 2. Thomas, D.L., et al., Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature, 2009. 461 (7265): p. 798–801, 3. Prokunina-Olsson, L., et al., A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet, 2013. 45 (2): p. 164–71.

Commentary: durability of SVR in chronic hepatitis C patients treated with peginterferon-a2a/ribavirin in combination with a direct-acting anti-viral - authors’ reply

139: 1593–601. 3. McCarthy JJ, Li JH, Thompson A, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology 2010; 138: 2307–14. 4. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401. 5. Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.

OP0186 Etiological therapy in HCV-related mixed cryoglobulinemia syndrome: The role of IL28B genotype as predictor of response

BackgroundMixed cryoglobulinemia syndrome (MCS) is a HCV-related, invalidating lymphoproliferative disorder (LPD) whose manifestations are related to a systemic vasculitis. The pathogenesis of MCS is a multistep process involving a strong...

894 FEMALE SEX AND VARIATIONS IN IL28B ARE INDEPENDENTLY ASSOCIATED WITH SPONTANEOUS CLEARANCE OF ACUTE HCV INFECTION

894 FEMALE SEX AND VARIATIONS IN IL28B ARE INDEPENDENTLY ASSOCIATED WITH SPONTANEOUS CLEARANCE OF ACUTE HCV INFECTION J. Grebely, G.J. Dore, M. Schim van der Loeff, T. Rice, A.L. Cox, J. Bruneau, A.Y. Kim, J. George, L. Maher, A.R. Lloyd, M. Hellard, K. Page, M. Prins, on behalf of the InC3 Collaborative Group. The Kirby Institute for Infection and Immunity in Society, University of New South Wales, Sydney, NSW, Australia; GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA; CRCHUM, Universite de Montreal, Montreal, QC, Canada; Harvard Medical School, Boston, MA, USA; Storr Liver Unit, Westmead Millennium Institute, University of Sydney, School of Medical Sciences, University of New South Wales, Sydney, NSW, Burnet Institute, Melbourne, VIC, Australia E-mail: jgrebely@kirby.unsw.edu.au

Genetic variation in IL28B is associated with the development of hepatitis B-related hepatocellular carcinoma.

To evaluate the role of host IL28B (interleukin 28B; interferon lambda 3) single nucleotide polymorphisms (SNPs) in predicting hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) susceptibility, three SNPs in the IL28B gene (rs12979860C/T, rs8099917G/T and rs12980275G/A) were examined in 330 subjects (including 154 HBV-related HCC patients, 86 non-HCC patients with chronic hepatitis B (CHB), 43 HBV self-limited infections and 47 healthy controls). Notably, the frequency of CC homozygosity was 91.5% in healthy controls and 72.9% in CHB, the difference being statistically significant (χ(2) = 6.40, P = 0.01). The statistically difference was seen between healthy controls (91.5%) and HCC (74.7%) (χ(2) = 6.05, P = 0.01). However, this significant finding was not seen between HBV self-limited and healthy controls. Carriers of the minor T allele in rs12979860 had a higher risk of HCC compared with non-carriers (χ(2) = 4.44, P = 0.04). Haplotype analyses revealed significant association between haplotype C-T-A and healthy controls, but not with the HCC group (96.6 vs. 82.0%, χ(2) = 6.08, P = 0.01). Analyses of genotype combination and gene-gene interaction showed that there was a positive interaction between rs12979860 and rs12980275, with an OR rate of 11.79 (likelihood test, P = 0.04). Our results suggest that the IL28B rs12979860 C/T polymorphism might affect susceptibility to the chronic HBV infection and progression of HCC. Of note, the T allele and non-CC genotypes have strong predictive effect of increasing susceptibility of chronic HBV infection and HCC.

Genetic Variations in IL28B and Allergic Disease in Children

Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences.

Genetic variation in IL28B and treatment outcome in HBeAg-positive and -negative chronic hepatitis B patients treated with Peg interferon alfa-2a and adefovir

In a cohort of 95 chronic hepatitis B patients, who were treated with peg-interferon and adefovir for 1 year, and who had 15% HBsAg loss (overall), no association was found between IL28B polymorphisms and HBeAg seroconversion or HBsAg clearance. These findings suggest that any association with outcome, if present, is less than that seen in chronic hepatitis C. Additional studies are needed to enlarge sample size and to refine our understanding of IL28B biology in the context of chronic hepatitis B response to immunomodulatory and direct antiviral therapy.

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.

Treatment of acute HCV infection

In developed nations, the majority of new HCV infections are acquired by injection drug users. Acute HCV infection is generally asymptomatic and is followed by spontaneous viral clearance in approximately 25% of individuals. However, given the asymptomatic nature of infection and difficulties in identifying and following those at risk of acquiring infection, our knowledge of treatment for acute HCV infection has been hampered. Much of what is known about the timing, optimal regimen and duration of therapy comes from small, prospective, observational studies and randomized, controlled trials in selected populations. Furthermore, data on the treatment of acute HCV infection among injection drug users and patients co-infected with HCV and HIV are limited. Genetic testing for variations in IL28B may provide an additional diagnostic tool for the optimal management and treatment of acute HCV infection. This Review highlights current knowledge of the epidemiology, diagnosis, natural history and treatment of acute HCV infection, including proposed recommendations for the assessment and treatment of this infection.

Genetic Variation in IL28B and Treatment-induced Clearance of Hepatitis C Virus in HIV-Positive Patients With Acute and Chronic Hepatitis C

Recently, a IL28B (rs 12979860) gene polymorphism was identified as a predictor for response to hepatitis C virus-specific treatment in human immunodeficiency virus (HIV)-uninfected and -infected patients with chronic hepatitis C. In an analysis of HIV-infected patients with acute hepatitis C, we found that the IL28B genotype was associated with serum levels of hepatitis C virus RNA, g-GT, and CD4 cell count. In contrast to HIV-infected patients with chronic hepatitis C, the IL28B genotype was not significantly associated with treatment response rates in patients with acute hepatitis C. Thus, effects of the IL28B single-nucleotide polymorphism may differ in HIV-infected patients with chronic and acute hepatitis C.

Focus

Focus

Novel Findings for the Development of Drug Therapy for Various Liver Diseases: Genetic Variation in IL-28B Is Associated With Response to the Therapy for Chronic Hepatitis C

Hepatitis C infection is a global health problem. Spontaneous viral clearance was observed in approximately 30% of individuals with acute infection. In the therapy using a combination of pegylated interferon-α and ribavirin, approximately 50% of chronic hepatitis C patients infected with high viremia of hepatitis C virus infection (HCV) genotype 1 reached a sustained viral response. These findings were strongly expected to reflect variations of the host genome. To reveal genetic effects against viral clearance or treatment response, four independent groups applied a genome-wide association study (GWAS) to HCV infection. These groups almost simultaneously reported a strong association of interleukin (IL)-28B polymorphisms with viral clearance or final decision of HCV therapy. The discovered single nucleotide polymorphisms (SNPs) also revealed the enigma that the viral clearance rate was dependent on ethnic type. The significant SNPs are useful for prediction prior to treatment because of the strong association with clinical outcome. In addition, the unexpected results revealed by GWAS could promote the development of a novel drug related to IL-28B. Herein, we present current understanding in regard to the relationship between host variations and clinical outcome of hepatitis C.

Genetic Variation in IL28B: Impact on Drug Development for Chronic Hepatitis C Infection

As more pharmacogenomic insights into diseases and their treatments and toxicities are published each year, the challenge arises to incorporate such insights into clinical practice and drug development. For instance, recent genomic discoveries related to hepatitis C offer a challenge to clinicians, researchers,and health administrators to translate this information into knowledge in order to develop safer and more effective therapeutic strategies for all patients.

SS7-5 Genetic variation in IL28B and hepatitis C outcomes

SS7-5 Genetic variation in IL28B and hepatitis C outcomes

OL-001 Association study of genetic variation in IL28B with the hepatitis C treatment-induced viral clearance in Chinese Han population

OL-001 Association study of genetic variation in IL28B with the hepatitis C treatment-induced viral clearance in Chinese Han population

Genetic Variation in Interleukin-28B Predicts Hepatitis C Treatment-Induced Viral Clearance in Genotype 1 Patients: The Dawn of a New Era?

Ge D, Fellay J, Thompson AJ, et al. (Institute for Genome Sciences and Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina). Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399–401.