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IL28B, HLA-C, and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort: A Cross-Sectional Study

Lookup NU author(s): Professor Margaret Bassendine, Dr David Sheridan



Background: To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%-50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control. Methods and Findings: We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 "G" was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27x10(-8), 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71x10(-14), 2.67-5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83x10(-6), 2.03-7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B. Conclusions: Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.

Publication metadata

Author(s): Suppiah V, Gaudieri S, Armstrong NJ, O'Connor KS, Berg T, Weltman M, Abate ML, Spengler U, Bassendine M, Dore GJ, Irving WL, Powell E, Hellard M, Riordan S, Matthews G, Sheridan D, Nattermann J, Smedile A, Muller T, Hammond E, Dunn D, Negro F, Bochud PY, Mallal S, Ahlenstiel G, Stewart GJ, George J, Booth DR, IHCGC

Publication type: Article

Publication status: Published

Journal: PLoS Medicine

Year: 2011

Volume: 8

Issue: 9

Print publication date: 01/09/2011

Date deposited: 01/12/2011

ISSN (electronic): 1549-1277

Publisher: Public Library of Science


DOI: 10.1371/journal.pmed.1001092


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Funder referenceFunder name
German Competence Network for Viral Hepatitis (Hep-Net)
Robert W. Storr Bequest
Australian National Health and Medical Research Council
01KI0791BMBF (German Ministry for Science and Education)
01 KI 0437German Ministry of Education and Research (BMBF)
G0502028Medical Research Council UK
M42H.W. and J. Hector Foundation
LPO0990067Australian Research Council