A Common Functional Polymorphism (C->A Substitution at Position -863) in the Promoter Region of the Tumour Necrosis Factor- (TNF- ) Gene Associated With Reduced Circulating Levels of TNF-

Abstract

Tumour necrosis factor-alpha (TNF-alpha) plays a key role in orchestrating the complex events involved in inflammation and immunity. Accordingly, TNF-alpha has been implicated in a wide range of autoimmune and infectious diseases, but also in conditions such as obesity and insulin resistance. The regulation of TNF-alpha expression in man is indicated to be partly genetically determined. We therefore screened a 1263 bp section of the proximal promoter of the TNF-alpha gene for common genetic variants affecting the transcriptional activity of the gene. Here we report the characterization of a common functional polymorphism in the promoter region of the TNF-alpha gene, a C-->A substitution at position -863. Electromobility shift assays provided evidence for a distinct difference in the binding of monocytic and hepatic nuclear factors to the -863C and -863A alleles. The rare -863A allele was associated with 31% lower transcriptional activity ( P < 0.001) in chloramphenicol acetyltransferase (CAT) reporter gene studies in human hepatoblastoma (HepG2) cells, indicating that the-863C/A polymorphism influences the basal rate of transcription of the TNF-alpha gene in vitro. Allele frequencies were 0.83/0.17 amongst 254 apparently healthy men of Swedish origin, aged 35-50 years. In 156 men, the -863C/A polymorphism was associated with the serum TNF-alpha concentration, carriers of the rare A allele having a significantly lower TNF-alpha level ( P < 0.05). It is concluded that the common-863C/A polymorphism in the promoter region of the TNF-alpha gene is functional in vitro in monocytic and hepatic cells and influences the serum TNF-alpha concentration in vivo in healthy middle-aged men.