title: Hepatic cell-type specific gene expression better predicts HCV treatment outcome than IL28B genotype.
abstract: OBJECTIVE
  Cell-type specific expression patterns of hepatic interferon-stimulated genes (ISGs) and single nucleotide polymorphisms (SNPs) near the IL28B gene are associated with response to interferon-based therapy in patients with chronic hepatitis C virus (HCV) infection. It is not known how the IL28B genotype influences the ISG expression pattern and which is a better predictor of treatment response.
  
  
  METHODS
  Patients at the Toronto Western Hospital Liver Centre with known outcome to interferon-based treatment for HCV infection were evaluated. Analysis included hepatic gene expression profile using complementary DNA microarrays, genotype at the IL28B SNP rs12979860, and immunostaining for human myxovirus A protein 1 (MxA) in hepatocytes and macrophages.
  
  
  RESULTS
  The level of ISG immunostaining in hepatic macrophages correlated inversely with that of hepatocytes and was strongly associated with treatment outcome. Gene expression profiles and the IL28B genotype were associated with treatment response, but only absence of MxA staining in macrophages accurately predicted nonresponse to treatment. The positive predictive value (PPV) of the IL28B genotype was 94% and the negative predictive value (NPV) was 51% (n = 209). For messenger RNA expression, the PPV was 94% and the NPV was 54% (n = 65). For detection of MxA in macrophages, the PPV was 60% and the NPV was 98% (n = 110). Of 53 patients with undetectable macrophage MxA staining, only one had a sustained virologic response. IL28B genotype was strongly associated with cell-type specific staining for MxA. There was a stepwise increase in macrophage staining and decrease in hepatocyte staining from the TT (lack of response) to CC SNP (associated with response) in IL28B. By logistic regression, after controlling for the presence of macrophage MxA staining, the IL28B genotype was no longer associated with treatment response.
  
  
  CONCLUSIONS
  The cell-type-specific expression pattern of ISGs varies among patients with different IL28B genotypes and is a strong predictor of response to interferon-based treatment.
authors.affiliation: University Health Network, Toronto, Ontario, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: McGilvray
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
authors.forename: Limin
authors.initials: L
authors.lastname: Chen
authors.forename: Venessa
authors.initials: V
authors.lastname: Pattullo
authors.forename: Maha
authors.initials: M
authors.lastname: Guindi
authors.forename: Sandra
authors.initials: S
authors.lastname: Fischer
authors.forename: Ivan
authors.initials: I
authors.lastname: Borozan
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.forename: Nazia
authors.initials: N
authors.lastname: Selzner
authors.forename: E Jenny
authors.initials: EJ
authors.lastname: Heathcote
authors.forename: Katherine
authors.initials: K
authors.lastname: Siminovitch
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis; D020869:Gene Expression Profiling; D005838:Genotype; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D064547:Myxovirus Resistance Proteins; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D019204:GTP-Binding Proteins; D007372:Interferons; D007378:Interleukins; D064547:Myxovirus Resistance Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579071:MX1 protein, human