Journal Article

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

Tiina Skoog, Ferdinand M. van't Hooft, Bengt Kallin, Stefan Jovinge, Susanna Boquist, Jan Nilsson, Per Eriksson and Anders Hamsten

in Human Molecular Genetics

Volume 8, issue 8, pages 1443-1449
Published in print August 1999 | ISSN: 0964-6906
Published online August 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.8.1443
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

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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.

Journal Article.  5425 words.  Illustrated.

Subjects: Genetics and Genomics

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