title: Association of TNF-alpha 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-alpha (TNF-alpha) 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-alpha 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-alpha 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-alpha promoter alleles that were previously reported to be associated with higher plasma levels, i.e. the presence of the -308A allele (TNF-alpha-308A/G or A/A) or the absence of the -863A (TNF-alpha-863C/C) variant, were strongly associated with the resolution of HBV infection in three alternative analyzing models, i.e. TNF-alpha-308G>A (P=0.01) and TNF-alpha-863C>A (P=0.003-0.14), respectively. Haplotype analysis also revealed that TNF-alpha 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-alpha might be an important factor, which might explain the variable outcome of HBV infection.
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul 110-744, Korea.
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.forename: Hyo-Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.forename: Chung Yong
authors.initials: CY
authors.lastname: Kim
authors.forename: Myoung Hee
authors.initials: MH
authors.lastname: Park
authors.forename: Lyoung Hyo
authors.initials: LH
authors.lastname: Kim
authors.forename: Byung Lae
authors.initials: BL
authors.lastname: Park
authors.forename: Hyoung Doo
authors.initials: HD
authors.lastname: Shin
mesh_terms: D000328:Adult; D000368:Aged; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006512:Hepatitis B Core Antigens / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D012744:Sex Ratio; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D014409:Tumor Necrosis Factor-alpha