-308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter

J Inflamm. 1995-1996;46(1):42-50.


Tumor necrosis factor (TNF) is recognized as a central mediator of sepsis, septic shock, and multiple organ failure. These host reactions are associated with increased TNF levels in circulation, presumably due to increased TNF production. A previously described nucleotide variation at position -308 in the promoter region of the human TNF gene was shown to be associated with the clinical outcome of malaria. In this study we addressed the relevance of the -308 polymorphism for expression of the human TNF gene in response to bacterial endo- toxin in vivo and in vitro. First, we typed 80 patients suffering from severe sepsis and 153 healthy individuals and found no association of the -308 variation with incidence of the disease. In contrast, the NcoI marker in the closely linked lymphotoxin-alpha (LT-alpha) gene showed association with survivaL This discrepancy can be explained by the linkage of the TNFB2(NcoI) allele to the common TNF1 (-308) allele. Second, we generated reporter gene constructs with the promoter deletions and with both -308 variation in the context of the extended human TNF promoter region. Although such constructs were highly inducible by lipopolysaccharide (LPS) in transient transfections into a macrophage cell line, the -308 variation had no significant effect on transcription, consistent with the promoter deletion study. We conclude that the functional consequence of the -308 polymorphism may be unrelated to transcriptional response of the TNF gene to bacterial endotoxin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Animals
  • Cell Line
  • Deoxyribonucleases, Type II Site-Specific
  • Gene Deletion
  • Heterozygote
  • Homozygote
  • Humans
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Middle Aged
  • Mutagenesis, Site-Directed
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic*
  • Sepsis / genetics*
  • Sepsis / mortality
  • Survival Rate
  • Tumor Necrosis Factor-alpha / genetics*


  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • endodeoxyribonuclease NcoI
  • Deoxyribonucleases, Type II Site-Specific