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. 2010 Dec;52(6):1888-96.
doi: 10.1002/hep.23912. Epub 2010 Oct 7.

IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C

Thomas J Urban  1 , Alexander J Thompson, Shelton S Bradrick, Jacques Fellay, Detlef Schuppan, Kenneth D Cronin, Linda Hong, Alexander McKenzie, Keyur Patel, Kevin V Shianna, John G McHutchison, David B Goldstein, Nezam Afdhal
Affiliations

IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C

Thomas J Urban et al. Hepatology. 2010 Dec.

Abstract

Genetic variation in the IL28B (interleukin 28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC) who were treated with peginterferon-α and ribavirin. We hypothesized that IL28B polymorphism is associated with intrahepatic expression of interferon-stimulated genes (ISGs), known to influence treatment outcome. IL28B genotyping (rs12979860) and whole-genome RNA expression were performed using liver biopsies from 61 North American patients with CHC. After correction for multiple testing (false discovery rate < 0.10), 164 transcripts were found to be differentially expressed by IL28B-type. The interferon signaling pathway was the most enriched canonical pathway differentially expressed by IL28B-type (P < 10(-5)), with most genes showing higher expression in livers of individuals carrying the poor-response IL28B-type. In 25 patients for which treatment response data were available, IL28B-type was associated with SVR (P = 0.0054). ISG expression was also associated with SVR; however, this was not independent of IL28B-type. Analysis of miR-122 expression in liver biopsies showed reduced miR-122 levels associated with poorer treatment outcome, independently of IL28B-type. No association was observed between IL28B-type and levels of liver IL28B or IL28A messenger RNA expression. IL28B protein sequence variants associated with rs12979860 were therefore investigated in vitro: no differences in ISG induction or inhibition of HCV replication were observed in Huh7.5 cells.

Conclusion: The good response IL28B variant was strongly associated with lower level ISG expression. The results suggest that IL28B genotype may explain the relationship between hepatic ISG expression and HCV treatment outcome, and this is independent of miR-122 expression. IL28B-type was not associated with intrahepatic IL28B messenger RNA expression in vivo. Further investigation of the precise molecular mechanism(s) by which IL28B genetic variation influences HCV outcomes is warranted.

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Figures

Figure 1
Figure 1
Hierarchical clustering of samples according to genes showing the greatest differences in expression between IL28B genotypes. For clarity, only probes with FDR-corrected p-value <0.1 and a fold-change of >1.5 or of <−1.5 were included in the dendogram. IL28B-CC samples have higher expression than CT and TT samples when probe is red and lower expression when probe is blue.
Figure 2
Figure 2
Pathway analysis showed that genes showing differential expression by IL28B-type clustered in the canonical interferon signaling pathway (FDR P value threshold=0.1). Several additional immune-related pathways reach significance in this analysis.
Figure 3
Figure 3
Relationship between hepatic miR-122 expression and SVR. Real-time PCR measurement of miR-122 expression in liver biopsies from patients with known treatment outcome showed improved response rate in individuals with higher miR-122 expression levels (p = 0.024 by ANOVA).
Figure 4
Figure 4
Relationship between IL28B genotype and IL28B mRNA expression in liver tissue. A real-time PCR assay specific for IL28B demonstrated the absence of association between IL28B genotype and IL28B mRNA expression (p = 0.58 by one-way ANOVA), consistent with the microarray expression data.
Figure 5
Figure 5
Kinetics of inhibition of HCV replication (A) and stimulation of MX1 expression (B) by recombinant variant IFN-λ3 proteins in HCV replication-competent Huh7.5 cells.
Figure 5
Figure 5
Kinetics of inhibition of HCV replication (A) and stimulation of MX1 expression (B) by recombinant variant IFN-λ3 proteins in HCV replication-competent Huh7.5 cells.
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