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.