Global transcriptional response to interferon is a determinant of HCV treatment outcome and is modified by race
✍ Scribed by Xiao-Song He; Xuhuai Ji; Matthew B. Hale; Ramsey Cheung; Aijaz Ahmed; Yaqian Guo; Garry P. Nolan; Lawrence M. Pfeffer; Teresa L. Wright; Neil Risch; Robert Tibshirani; Harry B. Greenberg
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 515 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
Interferon (IFN)-␣-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-␣ therapy and incubated the cells with or without IFN-␣ 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-␣ 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-␣. 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-␣ therapy are likely to act at the JAK-STAT pathway that controls transcription of downstream ISGs. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2006; 44:352-359.)
V arious interferon (IFN)-␣ preparations, some in combination with ribavirin, are currently the only treatment for chronic hepatitis C virus (HCV) infection approved by the US Food and Drug Administration. Two recently developed pegylated IFNs (PEG-IFNs), interferon PEG-IFN alpha-2b and PEG-IFN alpha-2a, have resulted in improved efficacy. However, the sustained virological response rates for patients infected with HCV genotype 1 and with high viral load, the most common profile in this country, remains less than 50%. 1,2 The sustained virological response rate has been shown to be associated with multiple viral and host factors. In particular, the response rate in black patients is significantly lower than that seen in white patients. [3][4][5][6][7][8] The underlying mechanisms that determine the efficacy of IFN-␣ in different patient populations are poorly understood. IFN initiates signals from the cell surface to the nucleus, resulting in the upregulated expression of multiple genes described as IFN-stimulated genes (ISGs). 9,10 It was recently reported that upregulated baseline expression of a set of ISGs in patients with chronic