title: -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.
abstract: 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.
authors.affiliation: Clinic for Anesthesiology and Intensive Care Medicine, Christian-Albrechts-University, Kiel, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Stuber
authors.forename: I A
authors.initials: IA
authors.lastname: Udalova
authors.forename: M
authors.initials: M
authors.lastname: Book
authors.forename: L N
authors.initials: LN
authors.lastname: Drutskaya
authors.forename: D V
authors.initials: DV
authors.lastname: Kuprash
authors.forename: R L
authors.initials: RL
authors.lastname: Turetskaya
authors.forename: F U
authors.initials: FU
authors.lastname: Schade
authors.forename: S A
authors.initials: SA
authors.lastname: Nedospasov
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D002460:Cell Line; D015252:Deoxyribonucleases, Type II Site-Specific; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D018805:Sepsis / Q000235:genetics* / Q000401:mortality; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C052380:endodeoxyribonuclease NcoI; D015252:Deoxyribonucleases, Type II Site-Specific