Polymorphism of the human TNF-alpha promoter - random variation or functional diversity?

As more and more polymorphisms are discovered in the genes encoding cytokin es, a crucial question is whether this polymorphism has any functional effe ct. One of the most widely studied cytokine genes in this respect is the ge ne encoding human TNF-alpha. Much of the literature investigating the issue of whether TNF-alpha promoter polymorphisms have any functional effect on TNF-alpha transcription or influence disease susceptibility appears to repo rt negative results, giving the appearance and leading some authors to conc lude that polymorphism at this locus is functionally silent and exists only because of linkage disequilibrium with selectable HLA alleles. This review presents a new analysis of the available data which suggests that polymorp hism in the TNF-alpha promoter is not randomly distributed and therefore th at it most likely does have some functional and selectable effect. Further, a comparison of available data suggests that there is more consensus in th e literature than may at first appear to be the case. (C) 2000 Elsevier Sci ence Ltd. All rights reserved.