Journal
PLOS MEDICINE
Volume 8, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pmed.1001092
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Funding
- Australian Research Council [LPO0990067]
- Robert W. Storr Bequest
- Australian National Health and Medical Research Council
- German Competence Network for Viral Hepatitis (Hep-Net)
- German Ministry of Education and Research (BMBF) [01 KI 0437]
- EU [LSHM-CT-2004-503359]
- BMBF [01KI0787]
- Medical Research Council UK [G0502028]
- BMBF (German Ministry for Science and Education) [01KI0791]
- H.W. and J. Hector Foundation [M42]
- Medical Research Council [G0502028] Funding Source: researchfish
- National Institute for Health Research [CL-2010-01-004] Funding Source: researchfish
- MRC [G0502028] Funding Source: UKRI
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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.
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