Interferon stimulates the expression of a number of genes encoding enzymes with antiviral activities, including myxovirus resistance-1 (MxA), 2-5-oligoadenylate synthetase 1 (OAS-1) and double-stranded RNA-dependent protein kinase (PKR). We examined whether polymorphisms in these genes influenced the outcome of hepatitis C virus (HCV) infection. We observed a lower frequency of the GG genotype at position À88 in the MxA gene promoter in self-limiting HCV infection (OR ¼ 0.56; 95% CI: 0.35-0.8; P ¼ 0.010) and in nonresponders to therapy (OR ¼ 0.49; 95% CI: 0.25-0.95; P ¼ 0.020). This genotype predominantly influenced the outcome of treatment in patients with viral genotype 1 (OR ¼ 0.22 95% CI: 0.07-0.67; P ¼ 0.002). A polymorphism in the 3 0 -untranslated region of the OAS-1 gene was associated with outcome of infection (GG genotype less frequent in self-limiting infection: OR ¼ 0.43; 95% CI: 0.21-0.86; P ¼ 0.010). A polymorphism at position À168 in the promoter region of the PKR gene was associated with self-limiting infection (CT genotype: OR ¼ 2.75; 95% CI: 1.45-5.24; P ¼ 0.002). Further associations were found with a CGG trinucleotide repeat in the 5 0 UTR region of the PKR gene. Polymorphisms in the interferon-induced genes, MxA, OAS-1 and PKR appear thus associated with HCV outcome.

The natural outcome and response to treatment in hepatitis C virus (HCV) infection varies between individuals. Whereas some variation may be attributable to viral and environmental variables, it is probable that host genetic background also plays a significant role. Interleukin (IL)-10 has a key function in the regulation of cellular immune responses and in the suppression of pro-inflammatory cytokine secretion. Functional polymorphisms in the IL-10 gene have been described. We investigated the role of these polymorphisms in the outcome of HCV infection, treatment response and development of fibrosis in a case-control association study. Self-limiting infection was associated with the IL-10 (-592) AA genotype (OR=2.05; P=0.028). Persistent infection was associated with the IL-10 (-1082) GG genotype (OR=0.48; P=0.018). Sustained response to interferon therapy was associated with the IL-10 (-1082) GG genotype (OR=2.28; P=0.005) and the haplotype GCC (OR=2.27; P=0.020). The IL-10 (-1082) AA genotype and the ATA/ATA and ACC/ACC homozygous haplotypes were more frequent among patients with rapid fibrosis. Furthermore, the microsatellites IL-10.R and IL-10.G were associated with interferon response with IL-10R.2 conveying susceptibility (OR=1.80; P=0.034), and IL-10R.3 and IL-10.G13 being protective (OR=0.47; P=0.003 and OR=0.59; P=0.042, respectively). We conclude that polymorphisms in the IL-10 promoter appear to have some influence on the outcome of HCV infection, treatment and development of fibrosis.

The effect of host genetic variation on the outcome of hepatitis C virus (HCV) infection and its treatment is poorly understood. The chemokine receptors CCR5, CCR2, and CCR3 and their ligands, RANTES, MCP-1, MCP-2, and MIP-1␣, are involved in the immune responses and the selective recruitment of lymphocytes to the liver in HCV infection. We studied 20 polymorphisms within these genes and investigated their association with persistent carriage of HCV, severity of liver disease, hepatic inflammation, and response to treatment in a large European cohort. Significant associations were found between CCR5-⌬32 and reduced portal inflammation (P ‫؍‬ H epatitis C virus (HCV) is a major global health problem with 1% to 2% of the world's population chronically infected. The prevalence of infection in the United Kingdom is approximately 0.5%, 1 but it is likely that this figure will continue to rise as more cases come to light. Persistent HCV infection has a very variable outcome, with 25% of those infected developing cirrhosis within 20 years, of whom 3% to 5% per year will proceed to hepatocellular carcinoma. A further 5% per year will develop liver failure, and 2% per year will die of a liver-related death. There is also a very variable response to treatment because only 40% of those treated with interferon alfa and ribavirin successfully clear the virus. 2,3 There are a number of epidemiologic and viral factors that influence susceptibility to persistent HCV infection, progression of HCV-related liver disease, and response to treatment, but host genetic factors are also influential. This study has examined 20 polymorphisms in the genes for the CC chemokine receptors (CCR) CCR5, CCR2, and CCR3 and their ligands, RANTES (regulated and normal T-cell expressed and secreted), MCP-1 (monocyte chemotactic protein), MCP-2, and MIP-1␣ (macrophage inflammatory protein), to try and elucidate their role in the immunopathologic outcome of HCV infection..Chemokines constitute a large family of small (8-10 kD) cytokines that are up-regulated in inflammation and whose effects are mediated by members of a family of 7 transmembrane domain, G protein-coupled receptors. 4 Their major role is in leukocyte migration and dependent processes such as immune surveillance and innate and adaptive immune responses. Chemokines have been