Human Molecular Genetics Advance Access originally published online on August 5, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 19 2541-2546
DOI: 10.1093/hmg/ddg262
© 2003 Oxford University Press
Association of TNF-
promoter polymorphisms with the clearance of hepatitis B virus infection
1Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea, 2Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea and 3Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, Korea
Received May 27, 2003; Revised July 17, 2003; Accepted July 30, 2003
The mechanisms underlying the resolution of hepatitis B virus (HBV) infection remain undetermined. Tumor necrosis factor-
(TNF-) 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- 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- 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- promoter alleles that were previously reported to be associated with higher plasma levels, i.e. the presence of the -308A allele (TNF--308A/G or A/A) or the absence of the -863A (TNF--863C/C) variant, were strongly associated with the resolution of HBV infection in three alternative analyzing models, i.e. TNF--308G>A (P=0.01) and TNF--863C>A (P=0.003–0.14), respectively. Haplotype analysis also revealed that TNF- 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- might be an important factor, which might explain the variable outcome of HBV infection.
* To whom correspondence should be addressed at: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul 110-744, Korea. Tel: +82 27457557; Fax: +82 27448243; Email: hsleemd{at}snu.ac.kr
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