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Tumor necrosis factor (TNF) is a critical mediator of host defense against infection but may cause severe pathology when produced in excess. Individuals vary in the amount of TNF produced when their peripheral blood mononuclear cells are stimulated in vitro, and family studies indicate that much of this variability is genetically determined. Since the TNF response to infection is partly regulated at the transcriptional level, TNF promoter polymorphisms have been the subject of intense interest as potential determinants of disease susceptibility. A single nucleotide polymorphism at nucleotide -308 relative to the transcriptional start site has been associated with susceptibility to severe malaria, leishmaniasis, scarring trachoma, and lepromatous leprosy. Some experimental data indicate that this polymorphism acts to upregulate TNF transcription, but this remains controversial. Detailed analysis of multiple genetic markers at this locus and more sophisticated investigations of TNF transcriptional regulation, in different cell types and with a wide range of stimuli, are required to understand the molecular basis of these disease associations.

Original publication

DOI

10.1046/j.1525-1381.1999.99237.x

Type

Journal article

Journal

Proceedings of the Association of American Physicians

Publication Date

07/1999

Volume

111

Pages

290 - 298

Addresses

Molecular Infectious Diseases Group, Institute of Molecula Medicine, University of Oxford, UK.

Keywords

Humans, Leprosy, Infection, Sepsis, HIV Infections, Malaria, Leishmaniasis, Mucocutaneous, Genetic Predisposition to Disease, Postoperative Complications, Tumor Necrosis Factor-alpha, HLA-DR3 Antigen, Case-Control Studies, Major Histocompatibility Complex, Transcription, Genetic, Gene Expression Regulation, Gene Frequency, Genotype, Lymphotoxin-alpha, Genetic Variation, Genetic Linkage