Association of TNF -α promoter polymorphisms with the clearance of hepatitis B virus infection

Abstract

The mechanisms underlying the resolution of hepatitis B virus (HBV) infection remain undetermined. Tumor necrosis factor-α (TNF-α) plays a pivotal role in host immune response to HBV, and the capacity for cytokine production in individuals has a major genetic component. The aim of this study was to examine whether TNF -α promotor polymorphisms are associated with the clearance of HBV infection. A total of 1400 Korean subjects were enrolled in two different groups: ‘chronic carrier group’ (CC; n =1109), who were repeatedly hepatitis B surface antigen (HBsAg)-positive, and ‘subjects who spontaneously recovered’ (SR; n =291), who were HBsAg-negative with antibodies to HBsAg and hepatitis B core antigen. TNF -α promoter polymorphisms at positions − 1031T > C , − 863C > A , − 857C > T , − 376G > A , − 308G > A , − 238G > A and − 163G > A were determined and the genotype distributions of the CC and SR groups were compared. The TNF -α promoter alleles that were previously reported to be associated with higher plasma levels, i.e. the presence of the − 308A allele ( TNF -α- 308A / G or A / A ) or the absence of the − 863A ( TNF -α- 863C / C ) variant, were strongly associated with the resolution of HBV infection in three alternative analyzing models, i.e. TNF -α- 308G > A ( P =0.01) and TNF -α- 863C > A ( P =0.003–0.14), respectively. Haplotype analysis also revealed that TNF -α haplotype 1 [− 1031T ; − 863C ; − 857C ; − 308G ; − 238G ; − 163G ] and haplotype 2 [− 1031C ; − 863A ; − 857C ; − 308G ; − 238G ; − 163G ] were significantly associated with HBV clearance, showing protective antibody production and persistent HBV infection, respectively ( P =0.003–0.02). Our findings imply that variations in the genes governing the levels of constitutive and inducible TNF-α might be an important factor, which might explain the variable outcome of HBV infection.