VARIATION IN THE TNF-ALPHA PROMOTER REGION ASSOCIATED WITH SUSCEPTIBILITY TO CEREBRAL MALARIA

TUMOUR-necrosis factor-alpha (TNF-alpha) is believed to have an import ant role in the pathogenesis of severe infectious disease(1) and fatal cerebral malaria is associated with high circulating levels of this c ytokine(2,3). In a large case-control study in Cambian children we fin d that homozygotes for the TNF2 allele, a variant of the TNF-alpha gen e promoter region(4), have a relative risk of 7 for death or severe ne urological 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 o f cytokine genes can affect the outcome of severe infection. The maint enance of the TNF2 allele at a gene frequency of 0.16 in The Gambia im plies that the increased risk of cerebral malaria in homozygotes is co unterbalanced by some biological advantage.