Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance

Ge, Dongliang; Fellay, Jacques; Thompson, Alexander; Simon, Jason S.; Shianna, Kevin V.; Urban, Thomas; Heinzen, Erin L.; Qiu, Ping; Bertelsen, Arthur H.; Muir, Andrew J.; Sulkowski, Mark S.; McHutchison, John G.; Goldstein, David B.

doi:10.1038/nature08309

Cited by 3,197 publications

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“…Genetic and functional studies have identified key molecules and processes involved in clearing HCV spontaneously and using interferon (IFN)‐α based therapies 3, 4, 5, 6, 7, 8, 9. These studies have implicated both innate and adaptive mechanisms in clearing HCV infection.…”

Section: Introductionmentioning

confidence: 99%

“…One of the most impressive findings from Gene Wide Association Studies (GWAS) to date has been the identification of single nuclear polymorphisms (SNPs) upstream of IFN‐λ3 which are protective against HCV chronicity and treatment failure 3, 4, 5, 6, 7. This has been fine mapped to the TT/‐G polymorphism at rs67272382 in a CpG island, which is in strong linkage disequilibrium with IFN‐λ3 and is most likely to be the causal variant, with the possibility of defining a new type 3 IFN, IFN‐λ4 10, 11.…”

Section: Introductionmentioning

confidence: 99%

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The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

et al. 2015

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Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)‐λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA‐C1C1 (P = 0.027), IFN‐λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA‐B (TapG:HLA‐B114D) (P = 0.007) and HLA‐DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ2 test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN‐λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA‐C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non‐interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

et al. 2015

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“…[3][4][5] The three genes encode IFN-k1 (IL29), IFN-k2 (IL28A), and IFN-k3 (IL28B). The same set of SNPs was subsequently associated with natural clearance of HCV.…”

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Hepatitis C pharmacogenetics: State of the art in 2010

Afdhal¹,

McHutchison²,

Zeuzem³

et al. 2011

Hepatology

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In 2009, a correlated set of polymorphisms in the region of the interleukin-28B (IL28B) gene were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with pegylated interferon-alfa and ribavirin. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. The link between IL28B genotype and HCV clearance may impact decisions regarding initiation of current therapy, the design and interpretation of clinical studies, the economics of treatment, and the process of regulatory approval for new anti-HCV therapeutic agents. (HEPATOLOGY 2011;53:336-345)

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“…Although recent findings indicate that the interleukin-28B polymorphism explains approximately half of the treatment differences between African American and white patients, other factors, including cholesterol levels and statin use, may also play a role in virological response. 2 Recent evidence from small retrospective studies suggests that elevated low-density lipoprotein (LDL) levels may be associated with higher SVR rates in patients infected with HCV genotype 1. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] In vitro data suggest that lipid-lowering agents (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins) may inhibit viral replication.…”

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Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy

et al. 2010

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Elevated low-density lipoprotein (LDL) levels and statin use have been associated with higher sustained virological response (SVR) rates in patients receiving chronic hepatitis C therapy. However, these relationships have not been well characterized in randomized controlled trials. Furthermore, little is known about the relationship between high-density lipoprotein (HDL) and virological response. To determine whether baseline LDL or HDL levels and statin use affect SVR rates, we retrospectively evaluated the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial, in which 3070 treatment-naive, hepatitis C virus (HCV) genotype 1-infected patients were treated for up to 48 weeks in one of the following arms: (1) peginterferon (PEG-IFN) alfa-2b at 1.5 lg/kg/week with ribavirin (RBV) at 800 to 1400 mg/day, (2) PEG-IFN alfa2b at 1.0 lg/kg/week with RBV at 800 to 1400 mg/day, or (3) PEG-IFN alfa-2a at 180 lg/week with RBV at 1000 to 1200 mg/day. Virological responses were assessed by pretreatment statin use and baseline elevated LDL levels (!130 mg/dL) or low HDL levels (<40 mg/dL for men and <50 mg/dL for women). In 1464 patients with baseline elevated LDL levels or low HDL levels, the SVR rate was significantly higher than that in patients with normal levels (44.9% versus 34.0%, P < 0.001). In 66 patients receiving a statin pretreatment, the SVR rate was higher than the rate of those not receiving it (53.0% versus 39.3%, P 5 0.02). In a multivariate logistic regression analysis using the stepwise selection method with baseline characteristics, a high LDL level [odds ratio (OR) 5 1.6, 95% confidence interval (CI) 5 1.4-1.8, P < 0.001], a low HDL level (OR 5 0.5, 95% CI 5 0.3-0.8, P 5 0.004), and statin use (OR 5 2.0, 95% CI 5 1.1-3.7, P 5 0.02) were independently associated with SVR. Conclusion: Baseline elevated LDL levels or low HDL levels and preemptive statin usage were associated with higher SVR rates. Prospective studies may be considered to explore the biological impact of these factors on HCV RNA replication and treatment response. (HEPATOLOGY 2010;52:864-874)

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Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance

Cited by 3,197 publications

References 18 publications

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

Hepatitis C pharmacogenetics: State of the art in 2010

Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy

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