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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




Journal article


Nature genetics

Publication Date





145 - 150


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


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