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

Abstract

Genetic variation in the IL28B region has been associated with sustained virological response (SVR) rates in chronic hepatitis C (CHC) patients 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 CHC patients. 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 mRNA 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 mRNA expression in vivo. Further investigation of the precise molecular mechanism(s) by which IL28B genetic variation influences HCV outcomes is warranted.

Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C

“…Previous studies suggested a low pretreatment hepatic miR-122 level may predict NR to IFN-based therapy (14,26) irrespective of serum or hepatic HCV RNA level (14,25). In this study, we consistently found no correlation between hepatic or serum miR-122 and serum HCV RNA level.…”

Hepatitis C pharmacogenetics: State of the art in 2010

“…4,5 However, in the SNP expression database http://humangenome.duke.edu/software, no difference in peripheral blood mononuclear cell expression of IL28B on the basis of rs12979860 genotype has been noted. In addition, in two independent studies, 22,23 no differences in levels of intrahepatic IL28B gene expression on the basis of IL28B genotype were observed. Further studies are needed to elucidate the causal variants and the biological mechanisms underlying the association between IL28B genotype and HCV treatment response.…”

“…Similarly, in RNA expression analyses from liver biopsies of 61 North American patients with chronic HCV, 164 transcripts were differentially expressed on the basis of rs12979860 genotype. 23 The IFN signaling pathway was the most enriched canonical pathway with differential expression (P < 10 À5 ), and most genes had higher expression in livers of individuals carrying the poor-response non-C/C genotypes.…”

Host–virus interactions in hepatitis B and hepatitis C infection

“…It has been shown that IFN-ks convey anti-HCV activity by inducing various ISGs [67]. Some investigators have been able to show that the expression of IL-28 in PBMCs was higher in subjects with the major IL-28B genotype than in those with the minor IL-28B genotype; however, the levels of IL-28 transcripts in liver tissue were comparable regardless of IL-28B genotype [68,69].…”