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INTERLEUKIN 28B
LATEST LITERATURE
1: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2010 Aug 30, 139(3)
Prediction of Response to Pegylated Interferon plus Ribavirin by IL28B Gene Variation in Patients Coinfected With HIV and Hepatitis C Virus.
[Abstract]Background. Variation in the IL28B gene is associated with sustained virologic response (SVR) to pegylated interferon plus ribavirin in hepatitis C virus (HCV)-monoinfected patients with genotype 1. Data on other genotypes and on patients coinfected with human immunodeficiency virus (HIV) and HCV are more limited. We aimed to assess the predictive ability of variations in the single-nucleotide polymorphism rs12979860 for SVR in HIV/HCV-coinfected patients, regardless of HCV genotype. Methods. The rs12979860 genotype was determined by polymerase chain reaction in 154 patients who had received therapy against HCV with pegylated interferon plus ribavirin. Results. rs12979860 genotype was TT in 20 patients (13%), TC in 66 patients (43%), and CC in 68 patients (44%). Rates of SVR in patients with genotype CC and in those with genotype TC or TT, according to HCV genotype, were, respectively, 50% and 17% ([Formula: see text]) in patients with genotype 1, 80% and 25% ([Formula: see text]) in patients with genotype 4, and 93% and 77% ([Formula: see text]) in patients with genotype 3. The median (interquartile range) low-density lipoprotein cholesterol level in patients with rs12979860 CC was 89 mg/dL (73-120 mg/dL) versus 75 mg/dL (55-91 mg/dL) ([Formula: see text]) in those with TC or TT. Independent predictors of SVR were HCV genotype 2-3 (odds ratio [OR], 13.98; 95% confidence interval [CI], 4.87-40.1; [Formula: see text]), rs12979860 CC (OR, 5.05; 95% CI, 2.04-12.5; [Formula: see text]), baseline plasma HCV RNA load of 600,000 IU/mL (OR, 1.99; 95% CI, 1.18-3.34; [Formula: see text]), and female sex (OR, 4.28; 95% CI, 1.08-16.96; [Formula: see text]). Conclusions. IL28B gene variations independently predict SVR in HIV/HCV-coinfected patients with HCV genotype 1 and non-genotype 1 HCV infection. The association between rs12979860 and plasma low-density lipoprotein cholesterol suggests that the system low-density lipoprotein ligand/receptor might be involved in the effect of this genotype.
2: Hepatology (Baltimore, Md.), 2010 Jul 29, 52(2)
Potential role for Interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection.
[Abstract]Polymorphisms in the IL28B (interleukin-28B) gene region are important in predicting outcome following therapy for chronic hepatitis C virus (HCV) infection. We evaluated the role of IL28B in spontaneous and treatment-induced clearance following recent HCV infection. The Australian Trial in Acute Hepatitis C (ATAHC) was a study of the natural history and treatment of recent HCV, as defined by positive anti-HCV antibody, preceded by either acute clinical HCV infection within the prior 12 months or seroconversion within the prior 24 months. Factors associated with spontaneous and treatment-induced HCV clearance, including variations in IL28B, were assessed. Among 163 participants, 132 were untreated (n = 52) or had persistent infection (infection duration >/=26 weeks) at treatment initiation (n = 80). Spontaneous clearance was observed in 23% (30 of 132 participants). In Cox proportional hazards analysis (without IL28B), HCV seroconversion illness with jaundice was the only factor predicting spontaneous clearance (adjusted hazards ratio = 2.86; 95% confidence interval = 1.24, 6.59; P = 0.014). Among participants with IL28B genotyping (n = 102 of 163 overall and 79 of 132 for the spontaneous clearance population), rs8099917 TT homozygosity (versus GT/GG) was the only factor independently predicting time to spontaneous clearance (adjusted hazard ratio = 3.78; 95% confidence interval = 1.04, 13.76; P = 0.044). Participants with seroconversion illness with jaundice were more frequently rs8099917 TT homozygotes than other (GG/GT) genotypes (32% versus 5%, P = 0.047). Among participants adherent to treatment and who had IL28B genotyping (n = 54), sustained virologic response was similar among TT homozygotes (18 of 29 participants, 62%) and those with GG/GT genotype (16 of 25, 64%, P = 0.884). Conclusion: During recent HCV infection, genetic variations in IL28B region were associated with spontaneous but not treatment-induced clearance. Early therapeutic intervention could be recommended for individuals with unfavorable IL28B genotypes. (HEPATOLOGY 2010;).
3: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2010 Aug 19,
Impact of IL28B genotype on the early and sustained virologic response in treatment-na?ve patients with chronic hepatitis C.
[Abstract]BACKGROUND & AIMS:: Single nucleotide polymorphisms (SNPs) in the gene that encodes interleukin (IL)28B predict response of patients with chronic Hepatitis C to antiviral therapy. We investigated the roles of polymorphisms rs12979860 and rs8099917 on the early virologic response of treatment-na?ve patients. METHODS:: SNPs rs12979860 and rs8099917 were identified by real-time PCR analysis of samples from 682 patients (genotype[GT]1=372, GT2/3=208, GT4=102) who were treated with 180 mug peg-interferon-alpha2a and 400 or 800 mg (GT2/3, depending on the protocol) or 1000-1200 mg (GT1/4) ribavirin/day. The duration of treatment was 24 (GT2/3) or 24-72 weeks (GT1/4). RESULTS:: The decrease in virus 24 hours after the first dose of interferon in patients with GT1/4 was greater in carriers of the C/C than of the T allele (mean GT1: 1.28+/-0.49 log IU/ml vs. 0.77+/-0.49; GT4: 1.60+/-0.59 vs.0.77+/-0.55; both P<0.001); the patients with the C/C allele also had higher rates of a rapid virologic response (RVR) (GT1: 38.3% vs. 11.6%; GT4: 76.5% vs. 23.5%, both P<0.001) and sustained virologic responses (SVR) (GT1: 79.1% vs. 43.2%; GT4: 85.3% vs. 44.1%, both P<0.001). In patients with GT2/3, the RVR was more frequent in carriers of rs12979860 C/C (75.3% vs. 52.6%, P<0.01) but SVR rates were similar between those with C/C and T (80.5% vs. 74.4%, P=0.31). Results for rs8099917 were comparable. The positive predictive value of rs12979860 C/C for SVR was higher than of rs8099917 T/T (80.5% vs. 71.6%). Overall, RVR was the best predictor of SVR. In patients that did not have GT1, IL28B polymorphisms did not affect the SVR, if RVR data were included in the multivariate analysis. CONCLUSION:: An early virologic response to peginterferon and ribavirin is more likely among carriers of IL28 polymorphisms rs12979860 C/C and rs8099917 T/T, which might underlie their high rates of SVR. Determination of the IL28B genotype and whether patients have a RVR might be used in future studies of patients with Hepatitis C virus genotypes 1 or 4.
4: Gastroenterology, 2010 Aug 11,
Variants in IL28B in liver recipients and donors correlate with response to peginterferon and ribavirin therapy for recurrent hepatitis C.
[Abstract]BACKGROUND & AIMS:: Patients with hepatitis C virus (HCV)-related liver disease frequently receive orthotopic liver transplantation (OLT), but recurrent hepatitis C is still a major cause of morbidity. Patients are treated with peg-interferon and ribavirin (PEG-IFN/RBV), which has significant side effects and is costly. We investigated genetic factors of the host, liver donor, and virus that might predict sensitivity of patients with recurrent hepatitis C to PEG-IFN/RBV. METHODS:: Liver samples were analyzed from 67 HCV-infected recipients and 41 liver donors. Liver recipient and donor DNA samples were screened for single nucleotide polymorphisms (SNPs) near the IL28B gene (rs12980275 and rs8099917) that affect sensitivity to PEG-IFN/RBV. HCV RNA was isolated from patients and analyzed for mutations in the core, the IFN sensitivity-determining region, and IFN/RBV resistance-determining regions in NS5A. RESULTS:: In liver recipients and donors, the IL28ReSNP rs8099917 was significantly associated with a sustained viral response (SVR; P=0.003 and P=0.025, respectively). Intra-hepatic expression of IL28 mRNA was significantly lower in recipients and donors that carried the minor alleles (T/G or T/T) in rs8099917 (P=0.010 and 0.009, respectively). Genetic analyses of IL28B in patients and donors and of the core and NS5A regions encoded by HCV RNA predicted a SVR with 83% sensitivity and 82% specificity; this was more effective than analysis of any single genetic feature. CONCLUSIONS:: In patients with recurrent HCV infection after OLT, combination analyses of SNPs of IL28B in recipient and donor tissues and of mutations in HCV RNA allow prediction of SVR to PEG-IFN/RBV therapy.
5: Journal of viral hepatitis, 2010 Jul 26, 139(2)
A tetra-primer amplification refractory mutation system polymerase chain reaction for the evaluation of rs12979860 IL28B genotype.
[Abstract]Summary. Recently, genome-wide association studies in patients affected by HCV infection have identified a strong association between sustained virological response to peg-interferon/ribavirin and spontaneous viral clearance and common single nucleotide polymorphisms (SNPs) near the IL28B gene, encoding for interferon-lambda-3. Thus, it is anticipated that IL28B genotype determination will be integrated in clinical practice to guide treatment decisions. Here, we describe a simple tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) for the evaluation of the rs12979860 C>T IL28B SNP, for which strong evidence of association with clinical outcomes has been collected in subjects of European descent. Valid genotypic data were obtained for over 99% of subjects analysed, and T-ARMS-PCR procedures were validated by the analysis of DNA samples of 164 patients with chronic HCV infection. In conclusion, this method allows rapid, reproducible, inexpensive and accurate detection of rs12979860 polymorphism without need of any special equipment and is also suitable for evaluation of a low number of samples on a routine basis.
6: Hepatology (Baltimore, Md.), 2010 Mar 26, 138(4)
Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin.
[Abstract]Genetic variation near the IL28B gene and substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG-IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the predictive factors of sustained virological response to a 12-week or 24-week regimen of triple therapy in 72 of 81 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 61% and 89%, respectively. Especially, the sustained virological response was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of sustained virological response. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished sustained virological response (84%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high sustained virological response (50%), and sustained virological response (12%) was the worst in patients who possessed both genotype non-TT and Gln70(His70). Conclusion: This study identified genetic variation near the IL28B gene and aa substitution of the core region as predictors of sustained virological response to a triple therapy of telaprevir/PEG-IFN/ribavirin in Japanese patients infected with HCV genotype 1b. (HEPATOLOGY 2010).
7: Gastroenterology, 2010 Jul 14, 52(2)
A Polymorphism Near IL28B Is Associated With Spontaneous Clearance of Acute Hepatitis C Virus and Jaundice.
[Abstract]BACKGROUND & AIMS:: A single nucleotide polymorphism (SNP) upstream of the IL28B gene has been associated with response of patients with chronic hepatitis C to therapy with pegylated interferon and ribavirin and also with spontaneous clearance of acute hepatitis C in a heterogeneous population. We analyzed the association between IL28B and the clinical presentation of acute hepatitis C virus (HCV) infection in a homogeneous population. METHODS:: We analyzed the SNP rs12979860 in 190 women from the German anti-D cohort (infected with HCV genotype 1b via contaminated rhesus prophylaxis) and its association with spontaneous clearance. Clinical data were available in 136 women with acute infection who were also evaluated for IL28B genotype. Based on results of a TaqMan polymerase chain reaction assay, the rs12979860 SNP genotypes studied were C/C, C/T, or T/T. RESULTS:: Spontaneous clearance was more common in patients with the C/C genotype (43/67; 64%) compared with C/T (22/90; 24%) or T/T (2/33; 6%) (P < .001). Jaundice during acute infection was more common among patients with C/C genotype (32.7%) than non-C/C patients (with C/T or T/T) (16.1%; P = .032). In C/C patients, jaundice during acute infection was not associated with an increased chance of spontaneous clearance (56.3%) compared with those without jaundice (60.6%). In contrast, in non-C/C patients, jaundice was associated with a higher likelihood of spontaneous clearance (42.9%) compared with those without jaundice (13.7%). CONCLUSIONS:: The SNP rs12979860 upstream of IL28B is associated with spontaneous clearance of HCV. Women with the C/T or T/T genotype who did not develop jaundice had a lower chance of spontaneous clearance of HCV infection.
8: Journal of gastroenterology, 2010 Jul 16,
IL28B in hepatitis C virus infection: translating pharmacogenomics into clinical practice.
[Abstract]Three landmark genome-wide association studies (GWAS) published in 2009 identified the interleukin (IL) 28B gene locus as pivotal to the pathogenesis of hepatitis C virus (HCV) infection. Polymorphisms near the IL28B gene not only predicted treatment-induced and spontaneous recovery from HCV infection, but they also explained, to some extent, the difference in response rates between Caucasians and African Americans to standard therapy with pegylated interferon and ribavirin. The revelation that IL28B, an innate cytokine, plays an essential role in the pathogenesis, outcomes, and treatment responses to HCV infection has triggered a gold rush and an ever increasing number of reports on the subject are being presented at international conferences and in scientific journals. This review will summarize currently available data on the clinical impact of IL28B polymorphisms on HCV infection and the potential mechanisms for its effects. It will conclude with a discussion on how the research observations may translate into clinical practice and drug development.
9: Gastroenterology, 2010 Jun 2, 52(1)
Interleukin-28B Polymorphism Determines Treatment Response of Patients With Hepatitis C Genotypes 2 or 3 Who Do Not Achieve a Rapid Virologic Response.
[Abstract]BACKGROUND & AIMS: Polymorphisms in the region of the interleukin (IL)-28B gene on chromosome 19 have been associated with peginterferon-alfa-induced clearance of genotype 1 hepatitis C virus (HCV); there are no data for patients with genotypes 2 or 3 HCV. We evaluated the effects of IL-28B polymorphisms on response to treatment with peginterferon and ribavirin in a well-characterized cohort of genotype 2/3 patients. METHODS: DNA was analyzed from 268 patients (Caucasian: genotype 2, 213; genotype 3, 55). Patients were randomly assigned to groups that received standard (24 wk; standard duration, 24 wk; n = 68) or variable durations of therapy. Patients who received variable durations (VD) and had a rapid virologic response (RVR) were treated for 12 weeks (VD12; n = 122); those without a RVR were treated for 24 weeks (VD24; n = 78). IL-28B genotypes (rs12979860) were analyzed for association with treatment response. RESULTS: The frequencies of the IL-28B genotypes were as follows: CC, 37%; CT, 48%; and TT, 15%; 82% of patients with the CC genotype achieved a sustained virologic response (SVR), compared with 75% with the CT and 58% with the TT genotypes (P = .0046). Differences between IL-28B genotypes were greatest among patients who failed to attain RVR (VD24 SVR rates: CC, 87%; CT, 67%; and TT, 29%; P = .0002). Among patients with RVRs (61%), the IL-28B genotype was not associated with SVR (>70% for all IL-28B genotypes). In a multivariable logistic regression model, IL-28B genotype predicted SVR (odds ratio, 1.76; 95% confidence interval, 1.16-2.7). CONCLUSIONS: An IL-28B polymorphism was associated with a SVR in patients infected with genotype 2/3 HCV who did not achieve a RVR. Analysis of IL-28B genotype might be used to guide treatment for these patients.
10: Gastroenterology, 2010 Apr 28, 24(8)
Genetic Variation in Interleukin-28B Predicts Hepatitis C Treatment-Induced Viral Clearance in Genotype 1 Patients: The Dawn of a New Era?
[Abstract]BACKGROUND: Given that peginterferon-ribavirin treatment is poorly tolerated, there is interest in the identification of predictors of response, particularly in HIV/hepatitis C virus (HCV)-coinfected patients that respond less than HCV-monoinfected individuals. A single nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) has been shown to predict treatment response in HCV-monoinfected patients carrying genotype 1. Information is lacking for HIV/HCV-coinfected individuals and/or other HCV genotypes. METHODS: From 650 HIV/HCV-coinfected patients, we identified those who had completed a course of peginterferon-ribavirin therapy with a validated outcome and available repository DNA. The rs12979860 SNP was examined in a blinded fashion. RESULTS: A total of 164 patients were included in the final IL28B genotyping analysis, 90 (55%) of whom achieved sustained virological response (SVR). HCV genotype distribution was as follows: HCV-1 58%, HCV-3 31% and HCV-4 11%. Overall, the SVR rate was higher in patients with CC than in those CT/TT genotypes: 56 of 75 (75%) versus 34 of 89 (38%) (P < 0.0001). The effect of the SNP was seen in HCV genotypes 1 and 4 but not in HCV genotype 3 carriers. In the multivariable analysis (odds ratio; 95% confidence interval; P value), the rs12979860 CC genotype was a strong predictor of SVR (3.7; 1.6-8.5; 0.002), independent of HCV genotype 3 (8.0; 3.1-21.0; <0.001), serum HCV-RNA less than 600,000 IU/ml (11.9; 3.8-37.4; <0.001) and lack of advanced liver fibrosis (3.5; 1.4-8.9; 0.009). CONCLUSION: The rs12979860 SNP located near the IL28B gene is associated with HCV treatment response in HIV-infected patients with chronic hepatitis C due to genotypes 1 or 4. Thus, IL28B genotyping should be considered as part of the treatment decision algorithm in this difficult-to-treat population.
11: Gastroenterology, 2010 Apr 28, 24(8)
Hepatic ISG expression is associated with genetic variation in IL28B and the outcome of IFN therapy for chronic hepatitis C.
[Abstract]OBJECTIVE:: Multiple viral and host factors are related to the treatment response to pegylated-interferon (Peg-IFN) and ribavirin (RBV) combination therapy; however, the clinical relevance and relationship of these factors have not yet been fully evaluated. METHODS:: We studied 168 patients with chronic hepatitis C who received Peg-IFN and RBV combination therapy. Gene expression profiles in the livers of 91 patients were analyzed using an Affymetrix genechip. The expression of interferon-stimulated genes (ISGs) was evaluated in all samples by real-time PCR. Genetic variation in interleukin 28B (IL28B; rs8099917) was determined in 91 patients. RESULTS:: Gene expression profiling of the liver differentiated patients into two groups: patients with up-regulated ISGs (Up-ISGs) and patients with down-regulated ISGs (Down-ISGs). A high proportion of patients with no response (NR) to treatment was found in the Up-ISGs group (p=0.002). Multivariate logistic regression analysis showed that ISGs (<3.5) (Odds=16.2, p<0.001), fibrosis stage (F1-2) (Odds=4.18, p=0.003), and ISDR mutation (>==2) (Odds=5.09, p=0.003) were strongly associated with the viral response. The IL28B polymorphism of 91 patients showed that 66% were major homozygotes (TT), 30% were heterozygotes (TG), and 4% were minor homozygotes (GG). Interestingly, hepatic ISGs were associated with the IL28B polymorphism (Odds=18.1, p<0.001) and its expression was significantly higher in patients with the minor genotype (TG or GG) than in those with the major genotype (TT). CONCLUSIONS:: The expression of hepatic ISGs is strongly associated with treatment response and genetic variation of IL28B. The differential role of host and viral factors as predicting factors may also be present.
12: AIDS (London, England), 2010 Apr 12,
Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.
[Abstract]BACKGROUND:: Given that peginterferon-ribavirin treatment is poorly tolerated, there is interest in the identification of predictors of response, particularly in HIV/hepatitis C virus (HCV)-coinfected patients that respond less than HCV-monoinfected individuals. A single nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) has been shown to predict treatment response in HCV-monoinfected patients carrying genotype 1. Information is lacking for HIV/HCV-coinfected individuals and/or other HCV genotypes. METHODS:: From 650 HIV/HCV-coinfected patients, we identified those who had completed a course of peginterferon-ribavirin therapy with a validated outcome and available repository DNA. The rs12979860 SNP was examined in a blinded fashion. RESULTS:: A total of 164 patients were included in the final IL28B genotyping analysis, 90 (55%) of whom achieved sustained virological response (SVR). HCV genotype distribution was as follows: HCV-1 58%, HCV-3 31% and HCV-4 11%. Overall, the SVR rate was higher in patients with CC than in those CT/TT genotypes: 56 of 75 (75%) versus 34 of 89 (38%) (P < 0.0001). The effect of the SNP was seen in HCV genotypes 1 and 4 but not in HCV genotype 3 carriers. In the multivariable analysis (odds ratio; 95% confidence interval; P value), the rs12979860 CC genotype was a strong predictor of SVR (3.7; 1.6-8.5; 0.002), independent of HCV genotype 3 (8.0; 3.1-21.0; <0.001), serum HCV-RNA less than 600 000 IU/ml (11.9; 3.8-37.4; <0.001) and lack of advanced liver fibrosis (3.5; 1.4-8.9; 0.009). CONCLUSION:: The rs12979860 SNP located near the IL28B gene is associated with HCV treatment response in HIV-infected patients with chronic hepatitis C due to genotypes 1 or 4. Thus, IL28B genotyping should be considered as part of the treatment decision algorithm in this difficult-to-treat population.
13: Gastroenterology, 2010 Feb 22,
Interleukin-28b: A Key Piece of the Hepatitis C Virus Recovery Puzzle.
[Abstract]
14: Gastroenterology, 2010 Feb 19,
Replicated Association between an IL28B Gene Variant and a Sustained Response to Pegylated Interferon and Ribavirin.
[Abstract]BACKGROUND & AIMS:: Patients with chronic hepatitis C virus (HCV) infections are treated with pegylated interferon and ribavirin (PEG-IFN/RBV), which is effective in less than 50% of those infected with HCV genotype 1. Genome-wide association studies have linked response to PEG-IFN/RBV with common single nucleotide polymorphisms in the vicinity of IFN-lambda genes on chromosome 19. We investigated the association between the polymorphism rs12979860 and treatment response in a diverse cohort of chronic HCV patients. METHODS:: A cross-sectional study was performed using data from 1021 consecutive patients enrolled in the Duke Hepatology Clinic Research Database and Biorepository. We analyzed DNA, clinical, and demographic data, along with validated data of the response of 231 subjects to PEG-IFN/RBV. The study included Caucasians (n=178), African Americans (n=53), and HCV genotypes 1 (n=186) and 2/3 (n=45). The rs12979860 genotype was tested for an association with sustained virologic response, defined as undetectable levels of HCV RNA 24 weeks after treatment ended. RESULTS:: The rs12979860 CC genotype (found in ~40% of Caucasians) predicted a sustained virologic response to therapy among Caucasians (odds ratio 5.79; 95% confidence interval 2.67-12.57; p=9.0 x 10(-6)), independent of HCV genotype and other covariates. Rs12979860 CC predicted a sustained response with 78% specificity and 65% sensitivity in patients infected with HCV genotype 1-better than HCV genotype (currently used to predict treatment response). CONCLUSIONS:: rs12979860 genotype is a significant independent predictor of response to PEG-IFN/RBV in patients with chronic HCV infection; tests for this genotype might be used to determine the best course of treatment for patients considering antiviral therapy.
15: Gastroenterology, 2010 Jan 7,
Genetic variation in IL28B Is Associated with Chronic Hepatitis C and Treatment Failure - A Genome-Wide Association Study.
[Abstract]BACKGROUND & AIMS:: The hepatitis C virus (HCV) induces chronic infection in 50%-80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy. METHODS:: The analysis included 1362 individuals; 1015 with chronic hepatitis C and 347 that spontaneously cleared the virus (448 were co-infected with HIV). Responses to pegylated interferon-alpha and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression. RESULTS:: Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon-lambda. The rs8099917minor allele was associated with progression to chronic HCV infection (OR=2.31, 95% confidence interval [CI]=1.74-3.06, P=6.07*10-9). The association was observed in HCV mono-infected (OR=2.49, 95% CI=1.64-3.79, P=1.96*10-5) and HCV/HIV co-infected individuals (OR=2.16, 95% CI=1.47-3.18, P=8.24*10-5). rs8099917 was also associated with failure to respond to therapy (OR=5.19, 95% CI=2.90-9.30, P= 3.11*10-8), with the strongest effects in patients with HCV genotypes 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients that responded to therapy, and 58% that did not respond (P=3.2*10-10). Re-sequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype. CONCLUSIONS:: The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon-lambda in the pathogenesis of HCV infection.
16: Nature genetics, 2009 Oct, 41(10)
Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.
[Abstract]The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).
17: Nature, 2009 Sep 17, 461(7262)
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.
[Abstract]Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.