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