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

A biallelic G (TNF1 allele) to A (TNF2 allele) polymorphism 308 nucleotides upstream from the transcription initiation site in the tumor necrosis fact or (TNF) promoter is associated with elevated TNF levels and disease suscep tibilities observed in human subjects. The TNF2 allele is strongly associat ed with the high-TNF-producing autoimmune MHC haplotype HLA-A1, B8, DR3, wi th elevated serum TNF levels and a more severe outcome in infectious diseas es, 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 stu dies 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 g ene assays in Raji B cells, Jurkat T cells, and U937 pre-monocytic cells, U p to fivefold differences can be measured between TNF1 and TNF2 allelic con structs when the TNF 3'UTR is present, indicating a role in the expression of the polymorphism, Although controversial, the majority of the data suppo rt a direct role for the TNF2 -308 allele in the elevated TNF levels observ ed in TNF2 homozygotes nd HLA-A1, B8, DR3 individuals, Elevated TNF levels due to the -308 polymorphism may alter tbe immune response such that it con fers susceptibility to certain autoimmune and infectious diseases.