RESUMEN
BACKGROUND: Two receptor chains, IL-10RA and IL-10RB, are known to mediate the functions of interleukin-10 (IL-10), which has been shown to be involved in the progression of persistent hepatitis C virus (HCV) infection. Little information is available on the role of host genetic variation in IL-10 receptor genes and outcome of HCV infection. IL-22, an IL-10 homologue, shares the IL-10RB receptor chain with IL-10 and has antiviral properties. We investigated the possible role of polymorphisms in the IL-10RA and IL-22 genes in hepatitis C disease pathogenesis. METHODS: This study population consisted of 631 HCV patients, recruited from several hepatology clinics across Europe. We genotyped four single-nucleotide polymorphisms (SNPs) in the IL-10RA and six SNPs in the IL-22 gene by ligation detection reaction or restriction fragment length polymorphism. Outcome of HCV infection was assessed according to viral clearance, treatment response, severity of fibrosis and overall inflammation. CONCLUSIONS: Variation in IL-10RA appeared to be correlated with response to treatment and inflammation. Two SNPs in IL-22 affected treatment response and viral clearance respectively. We furthermore report on allele and haplotype frequencies and linkage disequilibrium for IL-10RA and IL-22. Our results indicate that genetic variation in these genes may play a modulatory role in the outcome of hepatitis C infection.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Subunidad alfa del Receptor de Interleucina-10/genética , Interleucinas/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Casos y Controles , Análisis Mutacional de ADN , Europa (Continente) , Femenino , Frecuencia de los Genes , Haplotipos , Hepatitis C/genética , Humanos , Desequilibrio de Ligamiento , Masculino , Resultado del Tratamiento , Interleucina-22RESUMEN
Persistent hepatitis B virus infection is a major risk factor for hepatocellular carcinoma, the most frequent cancer in some developing countries. Up to 95% of those infected at birth and 15% of those infected after the neonatal period fail to clear hepatitis B virus, together resulting in approximately 350 million persistent carriers worldwide. Via a whole genome scan in Gambian families, we have identified a major susceptibility locus as a cluster of class II cytokine receptor genes on chromosome 21q22. Coding changes in two of these genes, the type I IFN receptor gene, IFN-AR2, and the IL-10RB gene that encodes a receptor chain for IL-10-related cytokines including the IFN-lambdas, are associated with viral clearance (haplotype P value = 0.0003), and in vitro assays support functional roles for these variants in receptor signaling.
Asunto(s)
Portador Sano , Hepatitis B Crónica , Proteínas de la Membrana/genética , Familia de Multigenes , Receptores de Interferón/genética , Receptores de Interleucina/genética , Carcinoma Hepatocelular/virología , Línea Celular , Gambia , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Hepatitis B Crónica/genética , Hepatitis B Crónica/inmunología , Humanos , Desequilibrio de Ligamiento , Neoplasias Hepáticas/virología , Proteínas de la Membrana/metabolismo , Polimorfismo Genético , Receptor de Interferón alfa y beta , Receptores de Citocinas , Receptores de Interferón/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina-10 , Análisis de Secuencia de ADN , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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-1alpha, 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-delta32 and reduced portal inflammation (P =.011, odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.09-4.84) and milder fibrosis (P =.015, OR: 1.97, 95% CI: 1.13-3.42). A promoter polymorphism at position -403 in the RANTES gene was associated with less severe portal inflammation (P =.004). An amino acid change in MCP2, Q46K, was associated with severity of fibrosis (P =.018, OR: 2.29, 95% CI: 1.14-4.58). In conclusion, our study suggests a possible role of the polymorphisms CCR5-delta32, RANTES -403, and MCP-2 Q46K in the outcome of HCV infection.
Asunto(s)
Quimiocina CCL5/genética , Hepatitis C/inmunología , Proteínas Quimioatrayentes de Monocitos/genética , Polimorfismo Genético , Receptores CCR5/genética , Secuencia de Bases , Quimiocina CCL8 , Femenino , Genotipo , Hepatitis C/genética , Hepatitis C/patología , Humanos , Cirrosis Hepática/patología , Masculino , Datos de Secuencia Molecular , Regiones Promotoras GenéticasRESUMEN
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.