A Polymorphism in IL28B Distinguishes Exposed, Uninfected Individuals From Spontaneous Resolvers of HCV Infection

Knapp, S.; Warshow, Usama; Ho, Ka-Kei; Hegazy, Doha; Little, Ann‐Margaret; Fowell, Andrew; Alexander, Graeme; Thursz, Mark; Cramp, Matthew; Khakoo, Salim I.

doi:10.1053/j.gastro.2011.04.005

Cited by 75 publications

(82 citation statements)

References 26 publications

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“…These include HLA‐I, HLA‐II, KIR, tapasin and IFN‐λ3/4 as described previously 9, 12, 14. Broadly speaking these represent a cellular innate immune response (IFN‐λ3/4), cytotoxic T‐lymphocytic response (HLA‐I and tapasin), T helper responses (HLA‐II) and NK cells (KIR), all of which have been implicated in the outcome of HCV infection.…”

Section: Resultsmentioning

confidence: 92%

“…SR was defined as the absence of HCV RNA, 6 months following a positive antibody test. HCV genotyping was performed using quantitative polymerase chain reaction (PCR) (iQur, Southampton, UK) 9, 12, 14.…”

Section: Methodsmentioning

confidence: 99%

“…Genotyping had previously been performed for KIR, IFN‐λ3/4 rs12979860, HLA and tapasin 9, 12, 14. Additional high resolution KIR genotyping was later performed on the patients with chronic HCV infection to accurately determine KIR copy number and impute KIR haplotype 25.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…In these studies it has been shown that for the SNPs associated with worse outcomes, KIR2DS3, HLA‐C2C2 and IFN‐λ3/4 (rs8099917 G allele and rs12979860 T allele), there appeared to be an interaction, as individuals with two susceptibility factors had significantly worse outcomes than those with only one 20, 21. Conversely no predictive benefit was found on combining the favorable IFN‐λ3/4 polymorphism with KIR2DL3:HLA‐C1 homozygosity for protection against viremia in seronegative exposed groups 12. On examination of the interaction of class I and II HLA alleles with KIR and IFN‐λ3/4 in the homogenous Irish HCV cohort and more heterogenous Swiss cohort, nothing further than an additive effect was seen 22.…”

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: Resultsmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2015

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Introduction to the genetics and biology of interleukin-28B

Charlton

Goldstein

2012

Hepatology

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Synergism of tapasin and human leukocyte antigens in resolving hepatitis C virus infection

et al. 2013

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CD8+ T cell responses to hepatitis C virus (HCV) are important in generating a successful immune response and spontaneously clearing infection. HLA class I presents viral peptides to CD8+ T cells to permit detection of infected cells, and tapasin is an important component of the peptide loading complex for HLA class I. We sought to determine if tapasin polymorphisms affected the outcome of HCV infection. Patients with resolved or chronic HCV infection were genotyped for the known C/G coding polymorphism in exon 4 of the tapasin gene. In a European, but not a US, Caucasian population, the tapasin G allele was significantly associated with outcome of HCV infection, being found in 82.5% of resolvers versus 71.3% of persistently infected individuals (p=0.02, OR=1.90 95% CI=1.11–3.23). This was more marked at the HLA-B locus at which heterozygosity of both tapasin and HLA-B was protective (p<0.03). Individuals with an HLA-B allele with an aspartate at residue 114 and the tapasin G allele were more likely to spontaneously resolve HCV infection (p<0.00003, OR=3.2 95%CI=1.6–6.6). Additionally individuals with chronic HCV and the combination of an HLA-B allele with an aspartate at residue 114 and the tapasin G allele also had stronger CD8+ T cell responses (p=0.02, OR=2.58, 95% CI-1.05–6.5). Conclusion Tapasin alleles contribute to the outcome of HCV infection by synergising with polymorphisms at HLA-B in a population specific manner. This polymorphism may be relevant for peptide vaccination strategies against HCV infection.

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A Polymorphism in IL28B Distinguishes Exposed, Uninfected Individuals From Spontaneous Resolvers of HCV Infection

Cited by 75 publications

References 26 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

Introduction to the genetics and biology of interleukin-28B

Synergism of tapasin and human leukocyte antigens in resolving hepatitis C virus infection

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