title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Vijayaprakash
authors.initials: V
authors.lastname: Suppiah
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Armstrong
authors.forename: Kate S
authors.initials: KS
authors.lastname: O'Connor
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Martin
authors.initials: M
authors.lastname: Weltman
authors.forename: Maria Lorena
authors.initials: ML
authors.lastname: Abate
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.forename: Margaret
authors.initials: M
authors.lastname: Bassendine
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.forename: William L
authors.initials: WL
authors.lastname: Irving
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Powell
authors.forename: Margaret
authors.initials: M
authors.lastname: Hellard
authors.forename: Stephen
authors.initials: S
authors.lastname: Riordan
authors.forename: Gail
authors.initials: G
authors.lastname: Matthews
authors.forename: David
authors.initials: D
authors.lastname: Sheridan
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.forename: Antonina
authors.initials: A
authors.lastname: Smedile
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Emma
authors.initials: E
authors.lastname: Hammond
authors.forename: David
authors.initials: D
authors.lastname: Dunn
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Golo
authors.initials: G
authors.lastname: Ahlenstiel
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Stewart
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
mesh_terms: D000328:Adult; D000483:Alleles; D000998:Antiviral Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015236:HLA-C Antigens / Q000235:genetics*; D016174:Hepacivirus / Q000276:immunology / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012367:RNA, Viral / Q000032:analysis; D054340:Receptors, KIR / Q000235:genetics; D054344:Receptors, KIR2DL3 / Q000235:genetics; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load; D044465:White People; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D015236:HLA-C Antigens; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D012367:RNA, Viral; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C515078:KIR2DL3 protein, human; C433932:KIR2DS2 protein, human