Tumor necrosis factor gene polymorphisms in patients with cirrhosis from chronic hepatitis C virus infection

Abstract

Pro-inflammatory cytokines including tumour necrosis factor (TNF) mediate the pathogenesis of hepatitis C virus (HCV) infection. The distribution of TNF gene polymorphisms was examined among cirrhotic and non-cirrhotic patients infected with HCV. Thirty Caucasians with cirrhosis due to chronic HCV infection and 114 HCV-infected patients histopathologically free of cirrhosis were genotyped for genetic variants in TNF, lymphotoxin ␣ and TNF-receptor type I using PCR-based techniques. Variability in the progression of HCV-related cirrhosis was assessed in a multivariate model including genetic and non-genetic factors such as gender, estimated duration of infection, alcohol consumption, and viral genotype. Viral genotype and non-genetic host features were not independently related to the occurrence or rate of development of cirrhosis in the patient population. In contrast, the TNF promoter variants TNF2 (−238A) and TNF3 (−308A) conferred a 3.2-fold and 5.1-fold risk of cirrhosis respectively (P = 0.03 for both). Reciprocal effects were observed with several TNF alleles and haplotypes defined by the −238G/A and −308G/A dimorphic sequences. Polymorphisms in the TNF␣ promoter appear to be associated with variability in the histological severity of chronic hepatitis C infection. Genes and Immunity (2000) 1, 386-390.

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.…”

“…The SNP À863C/C has been associated with viral persistence, 13 and the SNPs at À238 and À308 have had inconsistent associations with various HCV outcomes. [14][15][16] No association has been found between TNF SNPs and response to HCV treatment thus far. 17,18 The variability in these data may be due to the small size of these studies, examination of only a few of the known SNPs, and/or the different outcomes examined.…”

Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection

“…The lack of association between TNF and TNFc variants with differential therapeutic effects contrasted with our earlier findings that certain TNF variants conferred risk for cirrhosis in chronic HCV infection. 26 The effects mediated by polymorphism in cytokine regulatory elements may well differ at the early and late stages of infection. The mechanisms by which TNF operates in mediating the immune response may differ from those by which it enhances fibrogenesis.…”

“…25 Genotyping of TNF Ϫ238 and Ϫ308 promoter variants was performed by PCR with sequence-specific primers as reported previously. 26 Histologic Assessment. Liver biopsy specimens were available for 79 individuals and they were assessed for degree of liver fibrosis using the METAVIR system.…”

A novel nonsynonymous variant of matrix metalloproteinase-7 confers risk of liver cirrhosis

“…8 Previous studies regarding host genetic factors that are involved in liver fibrosis have been focused on inflammatory and immunoregulatory pathways. Tumor necrosis factor ␣, 9 transforming growth factor ␤1, 10 monocyte chemotactic protein-1, 11 and complement factor V 12 are well-known examples of factors associated with liver fibrosis. However, the effects of genetic polymorphisms that influence matrix turnover to fibrosis progression have not been examined.…”