Global transcriptional response to interferon is a determinant of HCV treatment outcome and is modified by race.
Interferon (IFN)-alpha-based therapy for chronic hepatitis C is effective in fewer than 50% of all treated patients, with a substantially lower response rate in black patients. The goal of this study was to investigate the underlying host transcriptional response associated with interferon treatment outcomes. We collected peripheral blood mononuclear cells from chronic hepatitis C patients before initiation of IFN-alpha therapy and incubated the cells with or without IFN-alpha for 6 hours, followed by microarray assay to identify IFN-induced gene transcription. The microarray datasets were analyzed statistically according to the patients' race and virological responses to subsequent IFN-alpha treatment. The global induction of IFN-stimulated genes (ISGs) was significantly greater in sustained virological responders compared with nonresponders and in white patients compared with black patients. In addition, a significantly greater global induction of ISGs was observed in sustained virological responders compared with nonresponders within the group of white patients. The level of IFN-induced signal transducer and activator of transcription (STAT) 1 activation, a key component of the Janus kinase (JAK)-STAT signaling pathway, correlated with the global induction of ISGs and was significantly higher in white patients than in black patients. In conclusion, both treatment outcome and race are associated with different transcriptional responses to IFN-alpha. Because this difference is evident in the global induction of ISGs rather than a selective effect on a subset of such genes, key factors affecting the outcome of IFN-alpha therapy are likely to act at the JAK-STAT pathway that controls transcription of downstream ISGs.
He
Xiao-Song
XS
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. xiaosong@stanford.edu
Ji
Xuhuai
X
Hale
Matthew B
MB
Cheung
Ramsey
R
Ahmed
Aijaz
A
Guo
Yaqian
Y
Nolan
Garry P
GP
Pfeffer
Lawrence M
LM
Wright
Teresa L
TL
Risch
Neil
N
Tibshirani
Robert
R
Greenberg
Harry B
HB
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D044383:Black People; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000208:ethnology / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects*; D014481:United States / Q000453:epidemiology; D044465:White People; D001741:Black or African American
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral