title: An interferon response gene signature is associated with the therapeutic response of hepatitis C patients.
abstract: Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFNα, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV. To characterize the response of HCV-infected patients to treatment with IFNα, the expression of an IFN-response gene signature comprised of IFN-stimulated genes and genes that play an important role in the innate immune response was examined in liver biopsies from HCV-infected patients enrolled in a clinical trial. In the present study we found that the expression of a subset of IFN-response genes was dysregulated in liver biopsy samples from nonresponsive hepatitis C patients as compared with virologic responders. Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients. We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Kui
authors.initials: K
authors.lastname: Li
authors.affiliation: The Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Jaquelyn F
authors.initials: JF
authors.lastname: Fleckenstein
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Tony N
authors.initials: TN
authors.lastname: Marion
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Diament
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Pfeffer
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Meiyun
authors.initials: M
authors.lastname: Fan
authors.affiliation: Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Handorf
authors.affiliation: Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Handorf
mesh_terms: D000328:Adult; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007372:Interferons / Q000494:pharmacology* / Q000627:therapeutic use; D007378:Interleukins / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D059467:Transcriptome / Q000187:drug effects*; D017211:Treatment Failure
chemical_list: D007378:Interleukins; D012254:Ribavirin; D007372:Interferons
references.citation: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references.pmid: 12184808
references.citation: Nature. 2006 Jul 6;442(7098):39-44
references.pmid: 16823444
references.citation: Hepatology. 2011 Dec;54(6):1913-23
references.pmid: 21800339
references.citation: Hepatology. 2004 Apr;39(4):1147-71
references.pmid: 15057920
references.citation: Nature. 2009 Sep 17;461(7262):399-401
references.pmid: 19684573
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D1040-6
references.pmid: 23203888
references.citation: Blood. 2004 Apr 1;103(7):2460-6
references.pmid: 14684419
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17717-22
references.pmid: 16301520
references.citation: J Biol Chem. 2010 Jul 23;285(30):22741-7
references.pmid: 20457596
references.citation: Gastroenterology. 2010 Aug;139(2):499-509
references.pmid: 20434452
references.citation: Hepatology. 2008 Mar;47(3):799-809
references.pmid: 18203148
references.citation: Hepatology. 2012 Mar;55(3):666-75
references.pmid: 22030901
references.citation: Nat Genet. 2009 Oct;41(10):1100-4
references.pmid: 19749758
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2992-7
references.pmid: 15710891
references.citation: J Virol. 2001 Aug;75(15):7059-66
references.pmid: 11435586
references.citation: Semin Immunopathol. 2013 Jan;35(1):53-72
references.pmid: 22868377
references.citation: Nature. 2008 Jul 24;454(7203):523-7
references.pmid: 18548002
references.citation: N Engl J Med. 2004 May 27;350(22):2265-71
references.pmid: 15163776
references.citation: Hepatology. 2005 Sep;42(3):702-10
references.pmid: 16108059
references.citation: J Clin Invest. 2010 Nov;120(11):4129-40
references.pmid: 20978355
references.citation: Gastroenterology. 2012 Apr;142(4):978-88
references.pmid: 22248663
references.citation: Hepatology. 2011 Oct;54(4):1433-44
references.pmid: 21898493
references.citation: New Biol. 1990 Oct;2(10):923-8
references.pmid: 1706625
references.citation: J Hepatol. 2013 Mar;58(3):564-74
references.pmid: 23063572
references.citation: PLoS Pathog. 2011 Oct;7(10):e1002289
references.pmid: 22022264
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):7034-9
references.pmid: 18467494
references.citation: Curr Gastroenterol Rep. 2004 Feb;6(1):66-70
references.pmid: 14720456
references.citation: J Interferon Cytokine Res. 2009 May;29(5):299-306
references.pmid: 19232000
references.citation: Gut. 2009 Jun;58(6):846-58
references.pmid: 19074178
references.citation: Cancer Res. 1998 Jun 15;58(12):2489-99
references.pmid: 9635566
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15669-74
references.pmid: 12441396
references.citation: J Mol Biol. 2014 Mar 20;426(6):1246-64
references.pmid: 24316048
references.citation: J Biol Chem. 2006 Apr 28;281(17):11678-84
references.pmid: 16517601
references.citation: Nature. 2009 Oct 8;461(7265):798-801
references.pmid: 19759533
references.citation: J Virol. 2009 Oct;83(19):9824-34
references.pmid: 19625408
references.citation: Cell Host Microbe. 2009 Dec 17;6(6):513-22
references.pmid: 20006840
references.citation: Nature. 2005 Aug 18;436(7053):939-45
references.pmid: 16107833
references.citation: Virology. 2011 Jan 20;409(2):175-88
references.pmid: 21036379
references.citation: Hepatology. 2007 Oct;46(4):999-1008
references.pmid: 17668868
references.citation: Gastroenterology. 2010 Apr;138(4):1338-45, 1345.e1-7
references.pmid: 20060832
references.citation: Hepatology. 2010 Dec;52(6):1888-96
references.pmid: 20931559
references.citation: Hepatology. 2012 Dec;56(6):2060-70
references.pmid: 22706965
references.citation: Eur J Med Res. 2012 May 11;17:9
references.pmid: 22577869
references.citation: J Biol Chem. 2004 Jul 23;279(30):31304-11
references.pmid: 15131130
references.citation: Nat Genet. 2009 Oct;41(10):1105-9
references.pmid: 19749757
references.citation: Gastroenterology. 2005 Jul;129(1):246-58
references.pmid: 16012951
references.citation: EMBO J. 1994 Jan 1;13(1):158-67
references.pmid: 8306959
references.citation: Hepatology. 2007 Nov;46(5):1548-63
references.pmid: 17929300
references.citation: RNA. 2002 Apr;8(4):512-25
references.pmid: 11991644
references.citation: Nature. 2005 Oct 20;437(7062):1167-72
references.pmid: 16177806
references.citation: J Interferon Cytokine Res. 2008 Sep;28(9):541-51
references.pmid: 18715197
references.citation: AIDS Res Hum Retroviruses. 1999 Jan 1;15(1):81-4
references.pmid: 10024057