IL 28 B , HLA-C , and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort : A Cross-Sectional Study

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 = 1.27610, 1.67–2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71610, 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 = 8.83610, 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. Please see later in the article for the Editors’ Summary. Citation: Suppiah V, Gaudieri S, Armstrong NJ, O’Connor KS, Berg T, et al. (2011) 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. PLoS Med 8(9): e1001092. doi:10.1371/journal.pmed. 1001092 Academic Editor: Paul Klenerman, University of Oxford, United Kingdom Received March 3, 2011; Accepted August 4, 2011; Published September 13, 2011 Copyright: 2011 Suppiah et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: VS, DB, GS, and JG were supported by Australian Research Council Roche Linkage Project grant LPO0990067 and the Robert W. Storr Bequest to the Sydney Clinical School, University of Sydney. GD is supported by an Australian National Health and Medical Research Council Practitioner Fellowship. TB is supported by the German Competence Network for Viral Hepatitis (Hep-Net), funded by the German Ministry of Education and Research (BMBF, Grant No. 01 KI 0437, Genetic host factors in viral hepatitis and Genetic Epidemiology Group in viral hepatitis) and by the EU-Vigilance network of excellence combating viral resistance (VIRGIL, Projekt No. LSHM-CT-2004-503359) as well as by the BMBF Project: Host and viral determinants for susceptibility and resistance to hepatitis C virus infection (Grant No. 01KI0787, Project B). DS and MB (Newcastle University, UK) are funded by a Medical Research Council UK project grant G0502028. JN was supported by BMBF (German Ministry for Science and Education) [grant no. 01KI0791] and H.W. and J. Hector Foundation [grant no. M42]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PLoS Medicine | www.plosmedicine. org 1 September 2011 | Volume 8 | Issue 9 | e1001092 Competing Interests: The authors have declared that no competing interests exist. Abbreviations: CHC, chronic hepatitis C; GWAS, genome-wide association study; HCV, hepatitis C virus; HLA-C, human leukocyte antigen C; IL28B, interleukin 28B; KIR, killer immunoglobulin-like receptors; LR, likelihood ratio; NK, natural killer; NSVR, no sustained viral response; OR, odds ratio; PegIFN/R, pegylated interferon-alpha and ribavirin; SC, spontaneous clearer; SVR, sustained viral response * E-mail: david_booth@wmi.usyd. edu.au " Contributing members of the International Hepatitis C Genetics Consortium (IHCGC) are listed in the Acknowledgments.