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

• DOI: 10.1371/journal.pmed.1001092
• Publication Date: 2011-09-13T17:27:53Z
• Authors: Vijayaprakash Sup...; Silvana Gaudieri; Nicola J. Armstrong; Kate S. O'Connor; Thomas Berg; Martin Weltman; Maria Lorena Abate; Ulrich Spengler; Margaret Bassendine; Gregory J. Dore; William L. Irving; Elizabeth Powell; Margaret Hellard; Stephen Riordan; Gail Matthews; David Sheridan; Jacob Nattermann; Antonina Smedile; Tobias Müller; Emma Hammond; David Dunn; Francesco Negro; Pierre-Yves Bochud; Simon Mallal; Golo Ahlenstiel; Graeme J. Stewart; Jacob George; David R. Booth
• Keywords: hepatitis C virus; Male; 0301 basic medicine; haplotypes; info:eu-repo/classification/ddc/616.07; NK cells; Hepacivirus; ddc:616.07; Cohort Studies; Interleukins/genetics; info:eu-repo/classification/ddc/616; Odds Ratio; Pharmacogenetics/methods; ddc:616; Antiviral Agents/therapeutic use; R; Interferon-alpha/therapeutic use; HLA-C Antigens/genetics; Viral Load; Middle Aged; 3. Good health; interferons; Killer Cells, Natural; Hepatitis C, Chronic/genetics/immunology/therapy/virology; Treatment Outcome; 2700 Medicine; Killer Cells, Natural/immunology; Medicine; Drug Therapy, Combination; Female; Hepacivirus/immunology/pathogenicity; Research Article; Adult; Genotype; European Continental Ancestry Group; Ribavirin/therapeutic use; Receptors, KIR/genetics; HLA-C Antigens; General & Internal; Polymorphism, Single Nucleotide; Antiviral Agents; 03 medical and health sciences; Predictive Value of Tests; General & Internal Medicine; XXXXXX - Unknown; 616; genotyping techniques; Humans; Alleles; Interleukins; Interferon-alpha; Hepatitis C, Chronic; Cross-Sectional Studies; genotyping; RNA, Viral/analysis; Case-Control Studies; Receptors, KIR2DL3/genetics; Interferons; hepatitis C; viral clearance; variant genotypes

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.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 = 1.27×10(-8), 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10(-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 = 8.83×10(-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.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.