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Genetic variation in cytokine promoter regions is postulated to influence susceptibility to infection, but the molecular mechanisms by which such polymorphisms might affect gene regulation are unknown. Through systematic DNA footprinting of the TNF (encoding tumour necrosis factor, TNF) promoter region, we have identified a single nucleotide polymorphism (SNP) that causes the helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles.

Original publication

DOI

10.1038/9649

Type

Journal

Nat Genet

Publication Date

06/1999

Volume

22

Pages

145 - 150

Keywords

Animals, Binding Sites, Child, DNA-Binding Proteins, Gambia, Gene Expression Regulation, Genetic Predisposition to Disease, Genotype, Host Cell Factor C1, Humans, Kenya, Malaria, Cerebral, Malaria, Falciparum, Monocytes, Octamer Transcription Factor-1, Plasmodium falciparum, Polymorphism, Genetic, Promoter Regions, Genetic, Receptors, Tumor Necrosis Factor, Reference Values, Regression Analysis, Transcription Factors