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

Tumor necrosis factor (TNF) is recognized as a central mediator of sep sis, septic shock, and multiple organ failure. These host reactions ar e associated with increased TNF levels in circulation, presumably due to increased TNF production. A previously described nucleotide variati on at position -308 in the promoter region of the human TNF gene was s hown to be associated with the clinical outcome of malaria. In this st udy we addressed the relevance of the -308 polymorphism for expression of the human TNF gene in response to bacterial endotoxin 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 variatio n with incidence of the disease. In contrast the NcoI marker in the cl osely linked lymphotoxin-alpha (LT-alpha) gene showed association with survival. This discrepancy can be explained by the linkage of the TNF B2 (NcoI) allele to the common TNF1 (-308) allele. Second toe generate d reporter gene constructs with promoter deletions and with both -308 variation in the context of the extended human TNF promoter region. Al though such constructs were highly inducible by lipopolysaccharide (LP S) in transient transfections into a macrophage cell line, the -308 va riation had no significant effect on transcription, consistent with th e 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. (C) 1996 Wiley-Liss, Inc.