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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
The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways
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)-?3/4, 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, ?2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA-C1C1 (P = 0.027), IFN-?3/4 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 (?2 test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN-?3/4 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.
hepatitis C, IFN-?3/4, immunogenetics, interferon, killer cell immunoglobulin receptors, tapasin
0001-2815
267-275
Hydes, T.J.
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Moesker, B.
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Traherne, J.A.
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Ashraf, S.
cd14ef70-7d2d-4e69-b02f-0d810fe14f89
Alexander, G.J.
a487266f-690c-4910-b3d2-86aae406f4e8
Dimitrov, B.D.
366d715f-ffd9-45a1-8415-65de5488472f
Woelk, C.H.
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Trowsdale, J.
ec6c3b7d-a688-4375-a61b-dbff47669777
Khakoo, S.I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273
Hydes, T.J.
d842d1ec-c64a-4934-a5a2-7316fea65767
Moesker, B.
73a0203e-b47b-4a20-9bbb-0e9ce9347789
Traherne, J.A.
e284d977-a35d-469c-9a17-01dafae825f2
Ashraf, S.
cd14ef70-7d2d-4e69-b02f-0d810fe14f89
Alexander, G.J.
a487266f-690c-4910-b3d2-86aae406f4e8
Dimitrov, B.D.
366d715f-ffd9-45a1-8415-65de5488472f
Woelk, C.H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Trowsdale, J.
ec6c3b7d-a688-4375-a61b-dbff47669777
Khakoo, S.I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273

Hydes, T.J., Moesker, B., Traherne, J.A., Ashraf, S., Alexander, G.J., Dimitrov, B.D., Woelk, C.H., Trowsdale, J. and Khakoo, S.I. (2015) The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways. Tissue Antigens, 86 (4), 267-275. (doi:10.1111/tan.12650). (PMID:26381047)

Record type: Article

Abstract

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)-?3/4, 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, ?2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA-C1C1 (P = 0.027), IFN-?3/4 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 (?2 test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN-?3/4 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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Accepted/In Press date: 10 August 2015
e-pub ahead of print date: 18 September 2015
Published date: October 2015
Keywords: hepatitis C, IFN-?3/4, immunogenetics, interferon, killer cell immunoglobulin receptors, tapasin
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 390061
URI: https://eprints.soton.ac.uk/id/eprint/390061
ISSN: 0001-2815
PURE UUID: 198fec97-5be0-4d37-95dd-0f6d9ef9f825

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Date deposited: 17 Mar 2016 15:34
Last modified: 06 Jul 2018 16:30

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