Tumour-necrosis factor-alpha (TNF-alpha) is believed to have an important role in the pathogenesis of severe infectious disease and fatal cerebral malaria is associated with high circulating levels of this cytokine. In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-alpha gene promoter region, have a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighbouring HLA alleles, we show that this disease association is independent of HLA class I and class II variation. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biological advantage.

Original publication

DOI

10.1038/371508a0

Type

Journal article

Journal

Nature

Publication Date

10/1994

Volume

371

Pages

508 - 510

Addresses

Department of Paediatrics, John Radcliffe Hospital, Oxford, UK.

Keywords

Animals, Humans, Plasmodium falciparum, Malaria, Cerebral, Genetic Predisposition to Disease, Tumor Necrosis Factor-alpha, DNA Primers, HLA Antigens, Histocompatibility Testing, Case-Control Studies, Base Sequence, Gene Frequency, Polymorphism, Genetic, Alleles, Molecular Sequence Data, Child, Child, Preschool, Infant, Gambia, Promoter Regions, Genetic