Background: The response to antiviral therapy of chronic hepatitis C virus (HCV) infection is determined by virological, environmental and genetic factors.
Objective: We have tested the hypothesis that the expression of specific genes and their haplotype frequencies can differentiate between non-responders (NRs) and sustained virological responders (SVRs) to antiviral treatment.
Methods: We used a methodological approach based on molecular marker-discovery and validation to study the genes influencing the antiviral treatment in lymphoblastoid cell lines from 74 genotype 1b hepatitis C virus patients (44 from Southern Italy and 30 from Northern Italy) treated with pegylated interferon-α and ribavirin. Furthermore, we performed an association study, testing three single nucleotide polymorphisms of SOCS3 in 162 NR and 184 SVR subjects [SOCS3 -8464 A/C (rs12952093), -4874 A/G (rs4969170), and 1383 A/G, (rs4969168)].
Results: SOCS3 basal expression levels were significantly increased in two independent sets of NR groups (P<0.05). We found a highly significant association between NRs and both the positively associated haplotype (OR=2.01, 95% CI: 1.45-2.79, P=0.0002) and the negatively associated haplotype (OR=0.56, 95% CI: 0.42-0.76, P=0.0014). In particular, the SOCS3 -4874 AA genotype was strongly associated with failure of antiviral therapy (OR=4.00, 95% CI: 2.09-7.66, P=0.0003) and the AA genotype carriers had significantly higher SOCS3 mRNA and protein levels (P<0.05).
Conclusions: Basal levels of SOCS3, an inhibitor of the interferon-α-induced Janus kinase-signal transducer and an activator of transcription pathways, and its genetic polymorphisms influence the outcome of antiviral treatment. SOCS3 thus represents a novel blood biomarker for the a priori prediction of treatment response.
- Hepatitis C
- antiviral therapy
- blood biomarkers