A common functional polymorphism (C -> A substitution at position-863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha

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 dise ases, but also in conditions such as obesity and insulin resistance. The re gulation of TNF-alpha expression in man is indicated to be partly genetical ly determined. We therefore screened a 1263 bp section of the proximal prom oter of the TNF-alpha gene for common genetic variants affecting the transc riptional activity of the gene. Here we report the characterization of a co mmon functional polymorphism in the promoter region of the TNF-alpha gene, a C-->A substitution at position -863, Electromobility shift assays provide d evidence for a distinct difference in the binding of monocytic and hepati c nuclear factors to the -863C and -863A alleles, The rare -863A allele was associated with 31% lower transcriptional activity (P < 0.001) in chloramp henicol acetyltransferase (CAT) reporter gene studies in human hepatoblasto ma (HepG2) cells, indicating that the -863C/A polymorphism influences the b asal rate of transcription of the TNF-alpha gene in vitro, Allele frequenci es were 0.83/0.17 amongst 254 apparently healthy men of Swedish origin, age d 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 sign ificantly 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 funct ional in vitro in monocytic and hepatic cells and influences the serum TNF- alpha concentration in vivo in healthy middle-aged men.