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Hepatitis C virus (HCV) is the major causal agent of non-A, non-B hepatitis and the leading indication for liver transplantation worldwide. The emerging field of immunogenetics has confirmed the significant role of heritability in host immune responses to infectious pathogens. Both the major and non-major histocompatibility complex genes are increasingly identified as candidate genes hypothesized to influence the susceptibility to, or the course of, a particular disease. We hypothesized that polymorphisms within the major histocompatibility complex class III region that encode for tumor necrosis factors (TNF)-α and TNF-β might be predictive of response to antiviral therapy in patients with chronic hepatitis C.A total of 155 subjects, including 110 HCV-seropositive individuals undergoing antiviral therapy and 45 ethnically similar HCV-negative controls, were studied. The HCV-positive patients had undergone antiviral treatment with either interferon monotherapy (n = 73) or in combination with ribavirin (n = 37) and were categorized as either nonresponders, sustained responders, or relapsers. Sixty (55%) patients had genotype 1 (1a or 1b). Genomic DNA was extracted, followed by polymerase chain reaction amplification and sequencing for two promoter TNF-α variants (at positions –238 and –308), as well as restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, aa26).Although there was a trend toward higher frequency of the A allele in the TNF 238 promoter among HCV-infected patients (12% vs 4%), there were no significant differences in the distribution of the genotypic polymorphisms between patients and controls. Patients with the TNF 238 A allele had higher pretreatment viral loads as compared with patients homozygous for the wild type allele (7.2 × 106 ± 4.2 × 106 copies/ml vs 3.8 × 106 ± 0.34 × 106 copies/ml, p = 0.03). However, there was no association between TNF genetic markers, including multiple haplotypic combinations, and response to therapy. In addition, there was no correlation with these polymorphic loci and histological severity of liver disease.Although previous work has suggested potential roles for TNF in the pathogenesis of HCV infection, we were unable to identify any link between TNF genetic polymorphisms and histological severity or response to antiviral therapy.