Polymorphisms in tumour necrosis factor‐α, transforming growth factor‐β, interleukin‐10, interleukin‐6, interferon‐γ, 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.

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

“…42,43 Generally, these are concentrated on the proximal IL10 promoter polymorphisms that have been associated with the differential IL-10 expression, 46,50 while other polymorphisms, particularly those in the distal part of the promoter, have also been implicated. 45 More recently, different proximal and distal polymorphism effects on IL-10 production have provided a more complex picture of gene expression.…”

“…37 Some of these studies indicate that there is a positive IL10 association with susceptibility to chronic hepatitis C infection and resistance to combined antiviral therapy [38][39][40][41] and rapid fibrosis 39 while in others the association between IL10 promoter region SNPs and viral clearance or persistent infection or severity of disease was not found. [42][43][44] These results further indicated the importance of evaluating HCV clearance in a large set of patients for IL10, its neighboring paralogs, and other genes in the region.…”

An analysis of tumor necrosis factor α gene polymorphisms and haplotypes with natural clearance of hepatitis C virus infection

“…14 Likewise, another study did not find the SNP at À308 to be associated with viral recovery or persistence. 21 À308A has been associated with increased cirrhosis in HCV-infected patients, 16 whereas À238A was Total number of black and white alleles assessed is two times the number of people in Table 1.…”

“…15 Studies of TNF polymorphisms and clearance of HCV in response to interferon-a therapy have also not studied the SNP at À863. [21][22][23] Given the findings in this study, it would be interesting to examine this polymorphism with respect to outcomes after treatment of chronic hepatitis C, which may facilitate a comparison between immune mechanisms involved in clearance either naturally or with therapy. Functional studies of the individual promoter SNPs at À863 and À308 have been inconsistent but indicate that these positions likely influence the production of TNF-a, which may in turn affect the outcome of an HCV infection.…”

Genetic polymorphism for IFNγ +874T/A in patients with acute toxoplasmosis

“…The influence of genetic background on the production of immunoregulatory cytokines in the clinical course and on the severity of disease manifestations has been the object of study in recent years 13,14 . With regard to toxoplasmosis, resistance to the development of RC was observed in association with specific genotypes of IL10 (-1082) 8 , IL1A (-889) 7 , and IFNγ (+874) 9 .…”