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

Abstract

Tumour necrosis factor-α (TNF-α) plays a key role in orchestrating the complex events involved in inflammation and immunity. Accordingly, TNF-α 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-α expression in man is indicated to be partly genetically determined. We therefore screened a 1263 bp section of the proximal promoter of the TNF-α 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-α 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-α 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-α concentration, carriers of the rare A allele having a significantly lower TNF-α level (P < 0.05). It is concluded that the common -863C/A polymorphism in the promoter region of the TNF-α gene is functional in vitro in monocytic and hepatic cells and influences the serum TNF-α concentration in vivo in healthy middle-aged men.