Cell-type specific gene expression signature in liver underlies response to interferon therapy in chronic hepatitis C infection.
OBJECTIVE
Chronic hepatitis C virus (CHC) infection is treated with interferon/ribavirin, but only a subset of patients respond. Treatment nonresponders have marked pretreatment up-regulation of a subset of interferon stimulated genes (ISGs) in their livers, including ISG15. We here study how the nonresponder gene expression phenotype is influenced by clinical factors and uncover the cellular basis of the phenotype through ISG15 protein expression.


METHODS
Seventy-eight CHC patients undergoing treatment were classified by clinical (gender, viral genotype, viral load, treatment outcome) and histologic (inflammation, fibrosis) factors and subjected to gene expression profiling on their pretreatment liver biopsies. An analysis of variance model was used to study the influence of individual factors on gene expression. ISG15 immunohistochemistry was performed on a subset of 31 liver biopsy specimens.


RESULTS
One hundred twenty-three genes were differentially expressed in the 78 CHC livers when compared with 20 normal livers (P < .001; fold change, > or =1.5-fold). Of genes influenced by a single factor, genotype (1 vs 2/3) influenced more genes (17) than any other variable; when treatment outcome was included in the analysis, this became the predominant influence (24 genes), and the effect of genotype was diminished. Treatment response was linked to cell-specific activation patterns: ISG15 protein up-regulation was more pronounced in hepatocytes in treatment nonresponders but in Kuppfer cells in responders.


CONCLUSIONS
Genotype is a surrogate marker for the nonresponder phenotype. This phenotype manifests as differential gene expression and is driven by activation of different cell types: hepatocytes in treatment nonresponders and macrophages in treatment responders.
Chen
Limin
L
Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada.
Borozan
Ivan
I
Sun
Jing
J
Guindi
Maha
M
Fischer
Sandra
S
Feld
Jordan
J
Anand
Nitasha
N
Heathcote
Jenny
J
Edwards
Aled M
AM
McGilvray
Ian D
ID
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001706:Biopsy; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D010641:Phenotype; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D019562:Viral Load
D000998:Antiviral Agents; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D014452:Ubiquitins; D011092:Polyethylene Glycols; D012254:Ribavirin; C074034:ISG15 protein, human; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a