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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.
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
URL: http://dx.doi.org/10.1371/journal.pmed.1001092
DOI: 10.1371/journal.pmed.1001092
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