The Impact of IL28B Genotype on the Gene Expression Profile of Patients with Chronic Hepatitis C (CH-C) Treated with Pegylated Interferon Alpha and Ribavirin (PEG-IFN/RBV)

Zobair M. Younossi, Aybike Birerdinc, Mike Estep, Maria Stepanova, Arian Afendi, V. Chandhoke, Ancha Baranova

This is a collaborative project between

School of Systems Biology, College of Science,George Mason University, Fairfax, VA

Translational Reseach Institute, Inova Hospital, VA

Common genetic variation within the IL28 locus has been found to influence the effect of peg-interferon and ribavirin combination therapy against chronic hepatitis C virus (HCV) infection. For the rs12979860 C>T IL28B SNP, a strong evidence of association with clinical outcomes has been collected in subjects of European descent. Despite the great strides in solidifying the association between IL28B genotypes and SVR, the exact underlying mechanism remains largely unknown. For IL28B genotyping, we employed a simple tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) (Galmozzi E et al., 2011). In an attempt to shed some light on the potential mechanism of the allelic association of IL28B with SVR, we assessed differential gene expression in CH-C patients according to their IL28B genotypes over the course of the PEG-IFN/RBV treatment.

Results
The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.

Conclusions
IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.

Manuscript is published in the BMC Journal of Translational Medicine