Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease.

Abstract

A biallelic G (TNF1 allele) to A (TNF2 allele) polymorphism 308 nucleotides upstream from the transcription initiation site in the tumor necrosis factor (TNF) promoter is associated with elevated TNF levels and disease susceptibilities observed in human subjects. The TNF2 allele is strongly associated with the high-TNF-producing autoimmune MHC haplotype HLA-A1, B8, DR3, with elevated serum TNF levels and a more severe outcome in infectious diseases, such as cerebral malaria. A number of groups have set out to determine whether the -308 polymorphism could affect transcription factor binding and hence influence TNF transcription and expression levels. Although some studies have failed to show any functional difference between the two allelic forms, others have shown that the -308 polymorphism effected transcription factor binding to the region encompassing -308, with the region in the TNF2 allele showing altered binding characteristics. The -308 polymorphism also has been found by some groups to be functionally significant in reporter gene assays in Raji B cells, Jurkat T cells, and U937 pre-monocytic cells. Up to fivefold differences can be measured between TNF1 and TNF2 allelic constructs when the TNF 3'UTR is present, indicating a role in the expression of the polymorphism. Although controversial, the majority of the data support a direct role for the TNF2 -308 allele in the elevated TNF levels observed in TNF2 homozygotes and HLA-A1, B8, DR3 individuals. Elevated TNF levels due to the -308 polymorphism may alter the immune response such that it confers susceptibility to certain autoimmune and infectious diseases.