A tumour necrosis factor-alpha (TNF-α) promoter polymorphism is associated with chronic hepatitis B infection

Abstract

Cytokines such as TNF-alpha and interferon gamma (IFN-gamma) are important for the elimination of infected hepatocytes during acute hepatitis B virus (HBV) infection. Two G versus A transitions in the TNF-alpha promoter region at positions -308 and -238 possibly influence TNF-alpha expression. We investigated these TNF-alpha polymorphisms in 71 patients with chronic HBV infection, in 32 subjects that had spontaneously recovered from acute HBV infection, and in 99 healthy controls. The -238 A promoter variant was present in 18 (25%) of 71 patients with chronic HBV infection compared with two (6%) of 32 subjects with acute infection (P<0.04), and seven (7%) of 99 controls (P<0.003). By contrast, the prevalence of the variant at position -308 was similar in all investigated groups. The observed differences could not be explained by linkage disequilibrium to HLA-B or -DRB1* alleles. These findings suggest an association between the TNF-alpha promoter polymorphism at position -238 and the development of chronic HBV infection. This promoter variant appears to be linked to defective viral clearance.

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

“…The TNF promoter variant −238A has previously been associated with failure to clear virus in both hepatitis B and hepatitis C infections, possibly due to altered TNF expression caused by a nucleotide substitution in a putative regulatory region of the promoter. 26,27 The −308A promoter variant has been associated with enhanced transcription of TNF, 16 but other investigations have failed to reproduce this finding. 24 Since TNF is located in the central MHC region where other polymorphic loci are abundant, it is possible that linkage disequilibria among genetic markers in the TNF and major histocompatibility complex (MHC) genes can offer the ultimate explanation for the disease associations we frequently encounter.…”

“…23 However, in the absence of plausible functional mechanisms these relationships may simply imply the strong linkage between TNF variants and others in neighboring regions. 17,24 The TNF pathway has been shown more recently to be involved in the immune response to viral hepatitis, [25][26][27] which prompted us to examine the distribution of common polymorphisms in the TNF system among HCVinfected patients.…”

Is there a future for TNF promoter polymorphisms?

“…101 Another study of 71 patients with chronic HBV infection found the À238A SNP to be associated with disease. 102 Various aspects of HCV disease have been studied with respect to TNF SNPs. Several studies have looked at response to therapy in HCV infected subjects, 103-110 using either interferon-alpha monotherapy or a combination of IFNa and ribavirin.…”

“…116,117 The latter study 117 is curious not because of the reported higher occurrence of the À238A allele among chronic HCV patients, but because the reported frequency in a healthy control group (n ¼ 99) drops from 7 117 to 3.5% in an article published concurrently by the same group. 102 Septic shock Due to the well-known role of TNF in sepsis, the prospect of identifying functional variants of this gene was very attractive. Sepsis patients may represent the tail end of the distributions for TNF production, making this population an excellent target for well-matched casecontrol studies.…”

Malaria infection and morbidity in infants in relation to genetic polymorphisms in Tanzania

“…Another genetic trait associated with various parasitic and infectious diseases (Cabrera et al 1995;Roy et al 1997;Hohler et al 1998) including malaria, is the TNF ␣ promotor polymorphism. Most importantly, children who are homozygous for the TNF ␣ promotor 2 allele (TNF2) suffer more from severe illness than children who are heterozygous or homozygous for the TNF ␣ promotor 1 allele (TNF1) (McGuire et al 1994).…”