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Background: Many factors contribute for viral clearance and response to antiviral therapy. Genetic polymorphisms of cytokines, chemokines, and their receptors can alter the immune response against Hepatitis C virus (HCV). Aim of the study: The aim of the current study is to assess single nucleotide polymorphism (SNP) in the promoter region of IL-10, TNF-α, IFN-γ and TGF-β as predictors of response to combined Pegylated interferon α/ribavirin (PEG–IFN/RBV) therapy in chronic HCV infected Egyptian patients. Patients and methods: The study was conducted on 150 HCV infected patients and 100 apparently healthy control subjects. All patients were treated with PEG–IFN/RBV. They were classified according to their response to treatment. Genotyping of IL-10, TNF-α, IFN-γ and TGF-β were performed on peripheral blood DNA using polymerase chain reaction–restriction fragment-length polymorphism (PCR–RFLP) and primer specific assays. Results: Overall, 83/150 (55.3%) patients achieved sustained virological response (SVR), whereas 67 (44.7%) did not. Age and BMI were significantly lower in patients who achieved SVR (P < 0.05). IL-10 at site (−1082) GG genotype was associated with SVR where odds ratio was 1.98 with 95% confidence interval (1.34–3.65). None of the other genes showed a significant association with SVR. Conclusion: Analysis of IL-10 SNP at promoter site (−1082) could be used as a pretreatment predictor of response to combined PEG–IFN/RBV treatment.