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Elevated expression and polymorphisms of SOCS3 influence patient response to antiviral therapy in chronic hepatitis C
  1. Marcello Persico
  1. Internal Medicine and Hepatology Unit, Second University of Naples, Italy
    1. Mario Capasso
    1. University Federico II of Naples, CEINGE - Biotecnologie Avanzate, Naples, Italy
      1. Roberta Russo
      1. University Federico II of Naples, CEINGE - Biotecnologie Avanzate, Naples, Italy
        1. Eliana Persico
        1. Internal Medicine and Hepatology Unit, Second University of Naples, Italy
          1. Lori Croce`
          1. Centro Studi Fegato, Trieste, Italy., Italy
            1. Claudio Tiribelli
            1. Centro Studi Fegato, Trieste, Italy., Italy
              1. Achille Iolascon (iolascon{at}ceinge.unina.it)
              1. University Federico II of Naples, CEINGE - Biotecnologie Avanzate, Naples, Italy

                Abstract

                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
                • SOCS3
                • antiviral therapy
                • blood biomarkers
                • polymorphisms

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