Polymorphisms in tumour necrosis factor-alpha, transforming growth factor-beta, interleukin-10, interleukin-6, interferon-gamma, and outcome of hepatitis C virus infection.

Abstract

Cytokines play a key role in the regulation of immune responses. In hepatitis C virus infection (HCV), the production of inappropriate cytokine levels appears to contribute to viral persistence and to affect response to therapy. Cytokine genes are polymorphic at specific sites, and certain mutations located within coding/regulatory regions have been shown to affect the overall expression and secretion of cytokines. The aim of this study was to investigate the frequency of genotypes associated with polymorphisms of TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma and to determine their association with the outcome of HCV infection. Genotyping was carried out by polymerase chain reaction sequence-specific primers on genomic DNA isolated from 158 individuals. Of these, 66 had spontaneously recovered from infection (persistently HCV RNA negative), while 92 had persistent infection (persistently HCV RNA positive). All patients were genotyped as high or low producers of TNF-alpha and IL-6 and high, intermediate, or low producers of TGF-beta, IL-10, and IFN-gamma based on single nucleotide substitutions. A significant proportion of patients with viral clearance were genotyped with a low IL-6 production profile, whereas those with persistent infection were genotyped with a high production profile (P = 0.02). No associations were observed between polymorphisms of TNF-alpha, IL-10, or IFN-gamma and viral clearance or persistent infection. Furthermore, there were no associations between cytokine genotypes and severity of disease. Inheritance of some genotypes associated with polymorphisms of cytokine genes, such as IL-6, may be host genetic factors associated with outcome of HCV in a well-defined ethnically homogeneous cohort.