IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy

Suppiah, Vijayaprakash; Moldovan, Max; Ahlenstiel, Golo; Berg, Thomas; Weltman, Martin; Abate, Maria Lorena; Bassendine, Margaret F.; Spengler, Ulrich; Dore, Gregory J.; Powell, Elizabeth E.; Riordan, Stephen M.; Sheridan, David; Smedile, Antonina; Fragomeli, Vincenzo; Müller, Tobias; Bahlo, Melanie; Stewart, Graeme J.; Booth, David R.; George, Jacob

doi:10.1038/ng.447

Cited by 1,721 publications

(1,680 citation statements)

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“…Thompson et al 8 reanalyzed the patient population from Ge et al 3 on an Tanaka et al 4 No. of patients 314 T/T 64** T/G 13 G/G 0 Suppiah et al 5 No. of patients 848 T/T 56 † † T/G 36 G/G 31…”

Section: Predictive Endpoints Of Il28b Snpsmentioning

confidence: 99%

See 1 more Smart Citation

Hepatitis C pharmacogenetics: State of the art in 2010

Afdhal¹,

McHutchison²,

Zeuzem³

et al. 2011

Hepatology

131

104

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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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Section: Predictive Endpoints Of Il28b Snpsmentioning

confidence: 99%

“…[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.…”

mentioning

confidence: 99%

Hepatitis C pharmacogenetics: State of the art in 2010

Afdhal¹,

McHutchison²,

Zeuzem³

et al. 2011

Hepatology

131

104

View full text Add to dashboard Cite

show abstract

“…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%

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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“…Genome-wide association studies have recently identified genetic variations near the IL28B gene, encoding for interferon (IFN)-k3, as a strong predictor of spontaneous and treatment-induced clearance of hepatitis C infection [13][14][15][16][17][18]. Protective variants at the rs12979860 and rs8099917 loci have consistently been associated with faster decline in viral load and an approximately twofold higher sustained virologic response rate during standard of care treatment, particularly, in patients affected by the difficult to cure HCV genotypes 1 and 4 [19,20].…”

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confidence: 99%

IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity?

2011

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Mutations in the core sequence of the HCV genome have been reported to influence treatment response, fibrosis progression, and hepatocarcinogenesis in Asian patients with genotype-1 chronic hepatitis C (CHC). In this issue, Miura et al. report data consistent with a causal relationship between the R70 ? Q70 core variant and hepatocellular carcinoma (HCC) risk in CHC genotype-1b patients, by the prospective evaluation of changes in the consensus sequence in the entire open reading frame between treatment failure and HCC development or end of follow-up, and validation of the initial findings in a confirmatory cohort. Furthermore, they observed an association between the IL28B genotype, which is believed to influence the immune response to viral infection, and the direction of time-dependent changes in core residue 70, with unfavorable IL28B genotypes linked to a preferential shift to the 70Q associated with HCC. Although this association needs to be validated in independent cohorts, and IL28B variants did not influence HCC risk, these results suggest that IL28B genotype might not only influence the behavior of the innate immune system in the presence of HCV genotype-1 infection but also shape the resultant viral evolution, with possible consequences on major clinical outcomes, such as HCC development, and treatment response.

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IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy

Cited by 1,721 publications

References 46 publications

Hepatitis C pharmacogenetics: State of the art in 2010

Hepatitis C pharmacogenetics: State of the art in 2010

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

IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity?

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