title: The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3.
abstract: BACKGROUND
  The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3.
  
  
  OBJECTIVE
  We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype.
  
  
  METHODS
  HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR.
  
  
  RESULTS
  Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV-1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype.
  
  
  CONCLUSIONS
  The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Holmes
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: M
authors.initials: M
authors.lastname: Congiu
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, The Doherty Institute, Melbourne, Vic., Australia.
authors.forename: S
authors.initials: S
authors.lastname: Bonanzinga
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: M K
authors.initials: MK
authors.lastname: Sandhu
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: Y H
authors.initials: YH
authors.lastname: Kia
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Bell
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: T
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: D M
authors.initials: DM
authors.lastname: Iser
authors.affiliation: Immunology Research Centre, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: K
authors.initials: K
authors.lastname: Visvanathan
authors.affiliation: Department of Gastroenterology, Monash Medical Centre, Monash University, Clayton, Vic., Australia.
authors.forename: W
authors.initials: W
authors.lastname: Sievert
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, The Doherty Institute, Melbourne, Vic., Australia.
authors.forename: D S
authors.initials: DS
authors.lastname: Bowden
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.
authors.forename: P V
authors.initials: PV
authors.lastname: Desmond
authors.affiliation: Department of Gastroenterology, St Vincent's Hospital, The University of Melbourne, Fitzroy, Vic., Australia.|Victorian Infectious Diseases Reference Laboratory, The Doherty Institute, Melbourne, Vic., Australia.|Department of Gastroenterology, Duke University Medical Centre, Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human