IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

Bibert, Stéphanie; Roger, Thierry; Calandra, Thierry; Bochud, Murielle; Cerny, Andreas; Semmo, Nasser; Duong, François H. T.; Gerlach, Tilman; Malinverni, Raffaele; Moradpour, Darius; Negro, Francesco; Müllhaupt, Beat; Bochud, Pierre‐Yves

doi:10.1084/jem.20130012

Cited by 188 publications

(221 citation statements)

References 27 publications

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“…A recent key discovery identified the IFNL4 gene and showed that a polymorphism (rs368234815), which causes the disruption of the IFNL4 reading frame, correlates with a substantially better treatment response 15,16 as well as better spontaneous clearance rate 13 . Thus, patients having a nonfunctional IFNL4 gene are more likely to clear the HCV infection.…”

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Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

et al. 2014

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Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNl4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNl4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNl4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNl4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.

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Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

et al. 2014

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“…However, none of these studies have exclusively examined this SNP in genotype 3 HCV patients.Besides these three studies, others have failed to show any significant association betweenIL28B polymorphisms and SVR in genotypes 2 and 3 HCV-infected patients 32 although all studies have shown an association with RVR. A recent report also shows significant association between a novelIL28B SNP (ss469415590; encoding IFN-L4) with SVR 33 in genotype 2/3 HCV infections.Therefore, the association of IL28B SNPs and SVR in genotype 2/3 HCV infections remains controversial. The present study shows that the rs8099917 SNP is associated with both RVR and SVR in genotype 3 patients, though the association is weak and shows no association with relapse.The latter is a relatively novel finding, and raises the need for larger studies to validate the role of IL28B polymorphism singenotype 3 treatment outcome.…”

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confidence: 91%

Association of IL28B single nucleotide polymorphism rs8099917 with response to treatment in genotype 3 HCV-infected patients from India

Chinnaswamy¹

2014

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“…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. Whilst this polymorphism has shown remarkable consistency in its ability to predict spontaneous and treatment‐induced viral clearance across populations, its protection does not extend to ‘exposed uninfected’ individuals, suggesting that multiple pathways to clearance may coexist within a population 12, 13.…”

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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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IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

Abstract: A new polymorphism near the IL28B locus negatively affects induction of IL28B and exhibits strong predictive value for HCV treatment response and spontaneous resolution.

Cited by 188 publications

References 27 publications

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Association of IL28B single nucleotide polymorphism rs8099917 with response to treatment in genotype 3 HCV-infected patients from India

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

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