title: Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C.
abstract: BACKGROUND
  Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)-α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome.
  
  
  METHODS
  Using microarray, we quantified the expression profile of 237 IFN related genes in 87 CH liver biopsy specimens to clarify the relationship between IFN pathway and viral elimination, and to predict patients' clinical outcome. In 72 out of 87 patients we also analyzed IL28B polymorphism (rs8099917).
  
  
  RESULTS
  Five IFN related-genes (IFI27, IFI 44, ISG15, MX1, and OAS1) had expression levels significantly higher in nonresponders (NR) than in normal liver (NL) and sustained virological responders (SVR); this high expression was also frequently seen in cases with the minor (TG or GG) IL28B genotype. The expression pattern of 31 IFN related-genes also differed significantly between NR and NL. We predicted drug response in NR with 86.1% accuracy by diagonal linear discriminant analysis (DLDA).
  
  
  CONCLUSIONS
  IFN system dysregulation before treatment was associated with poor IFN therapy response. Determining IFN related-gene expression pattern based on patients' response to combination therapy, allowed us to predict drug response with high accuracy. This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.
authors: Institute for Viral Research and Graduate School of Bioscience, Kyoto University, Kyoto, Japan.
authors: Koji
authors: K
authors: Onomoto
authors: Shiho
authors: S
authors: Morimoto
authors: Takahisa
authors: T
authors: Kawaguchi
authors: Hidenori
authors: H
authors: Toyoda
authors: Masami
authors: M
authors: Tanaka
authors: Masahiko
authors: M
authors: Kuroda
authors: Kazuko
authors: K
authors: Uno
authors: Takashi
authors: T
authors: Kumada
authors: Fumihiko
authors: F
authors: Matsuda
authors: Kunitada
authors: K
authors: Shimotohno
authors: Takashi
authors: T
authors: Fujita
authors: Yoshiki
authors: Y
authors: Murakami
references: Intervirology. 2006;49(1-2):82-90
references: 16166794
references: Gastroenterology. 2011 Mar;140(3):1021-31
references: 21111740
references: Hepatology. 2007 Oct;46(4):1279-90
references: 17886338
references: J Biol Chem. 2002 Jun 14;277(24):21829-35
references: 11916975
references: Proc Natl Acad Sci U S A. 2008 May 13;105(19):7034-9
references: 18467494
references: Liver Transpl. 2007 Aug;13(8):1100-8
references: 17377914
references: Gut. 2009 Jul;58(7):964-73
references: 19193669
references: PLoS Biol. 2004 Apr;2(4):E108
references: 15094809
references: Gastroenterology. 2010 Mar;138(3):1123-33.e1-3
references: 19900446
references: Swiss Med Wkly. 2010 Jan 9;140(1-2):3-11
references: 19950038
references: World J Gastroenterol. 2005 Dec 14;11(46):7330-4
references: 16437637
references: J Virol. 2009 Nov;83(21):11175-87
references: 19692459
references: Nat Genet. 2009 Oct;41(10):1105-9
references: 19749757
references: Nature. 2007 Aug 16;448(7155):816-9
references: 17653195
references: Hepatology. 2007 Nov;46(5):1548-63
references: 17929300
references: Minerva Gastroenterol Dietol. 2006 Jun;52(2):135-43
references: 16557185
references: Gastroenterology. 2010 Aug;139(2):499-509
references: 20434452
references: Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9010-5
references: 19451644
references: Gastroenterology. 2005 May;128(5):1437-44
references: 15887125
references: Annu Rev Pathol. 2006;1:23-61
references: 18039107
references: Nat Genet. 2009 Oct;41(10):1100-4
references: 19749758
references: Nature. 2009 Sep 17;461(7262):399-401
references: 19684573
references: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1440-5
references: 16434471
references: J Hepatol. 2007 Mar;46(3):403-10
references: 17126448
references: Gut. 2008 Apr;57(4):516-24
references: 17895355
references: Hepatology. 2009 Mar;49(3):763-74
references: 19140155
references: Hepatology. 2004 Aug;40(2):335-45
references: 15368438
references: Transl Res. 2007 Aug;150(2):116-21
references: 17656331
references: Curr Opin Immunol. 2008 Feb;20(1):61-7
references: 18082389
references: J Virol. 2001 Feb;75(3):1332-8
references: 11152506
references: BMC Med Genomics. 2010 Oct 22;3:48
references: 20969775
references: N Engl J Med. 2002 Sep 26;347(13):975-82
references: 12324553
references: N Engl J Med. 1996 Jan 11;334(2):77-81
references: 8531962