Nature 371, 508 - 511 (06 October 1994); doi:10.1038/371508a0

Variation in the TNF- promoter region associated with susceptibility to cerebral malaria

William McGuire, Adrian V. S. Hill^*, Catherine E. M. Allsopp ^*, Brian M. Greenwood^† & Dominic Kwiatkowski

Department of Paediatrics and ^* Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford 0X3 9DU, UK
^† Medical Research Council Laboratories, Fajara, The Gambia

TUMOUR-necrosis factor- (TNF-) is believed to have an important role in the pathogenesis of severe infectious disease¹ and fatal cerebral malaria is associated with high circulating levels of this cytokine^2,3. In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-a gene promoter region4, 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.

References

1.	Beutler, B. & Cerami, A. Nature 320, 584−588 (1986). | Article | PubMed | ISI | ChemPort |
2.	Grau, G. E. et al. New Engl. J. Med. 320, 1586−1591 (1989). | PubMed | ChemPort |
3.	Kwiatkowski, D. et al. Lancet 336, 1201−1204 (1990). | Article | PubMed | ISI | ChemPort |
4.	Wilson, A. G., di Giovine, F. S., Blakemore, A. I. F. & Duff, G. W. Hum. molec. Genet. 1, 353 (1992). | PubMed | ChemPort |
5.	Kwiatkowski, D. et al. Clin. exp. Immun. 77, 361−366 (1989). | PubMed | ChemPort |
6.	Kern, P., Hemmer, C. J., van Damme, J., Gruss, H.-J. & Dietrich, M. Am. J. Med. 57, 139−143 (1989).
7.	Clark, I. A. Parasitol. Today 3, 300−305 (1987). | Article | PubMed | ISI | ChemPort |
8.	Grau, G. E. et al. Science 237, 1210−1212 (1987). | PubMed | ISI | ChemPort |
9.	Berendt, A. R., Simmons, D. L., Tansey, J., Newbold, C. I. & Marsh, K. Nature 341, 57−59 (1989). | Article | PubMed | ISI | ChemPort |
10.	Clark, I. A., Rockett, K. A. & Cowden, W. B. Lancet 340, 894−895 (1992). | Article | PubMed | ChemPort |
11.	Molvig, J. et al. Scand. J. Immun. 27, 705−716 (1988). | ChemPort |
12.	Jacob, C. O. et al. Proc. natn. Acad. Sci. U.S.A. 87, 1233−1237 (1990). | ChemPort |
13.	Pociot, F. et al. Eur. J. Immun. 23, 224−231 (1993). | ChemPort |
14.	Wilson, A. G. et al. J. exp. Med. 177, 557−560 (1993). | Article | PubMed | ISI | ChemPort |
15.	Wilson, A. G., Symons, J. A., McDowell, T. L., di Giovine, F. S. & Duff, G. W. Br. J. Rheumatol. 33 (suppl. 1), 89 (1994).
16.	Kwiatkowski, D. Curr. Opin. Immun. 4, 425−431 (1992). | ChemPort |
17.	Alfonso, S. D. & Richiardi, P. M. Immunogenetics 30, 150−154 (1994).
18.	Goldfeld, A. E., Strominger, J. L. & Doyle, C. J. exp. Med. 174, 73−81 (1991). | Article | PubMed | ChemPort |
19.	Goldfeld, A. E., Doyle, C. & Maniatis, T. Proc. natn, Acad. Sci. U.S.A. 87, 9769−9773 (1990). | ChemPort |
20.	Rhoades, K. L., Golub, S. H. & Economou, J. S. J. biol. Chem. 267, 22102−22107 (1992). | PubMed | ISI | ChemPort |
21.	Dunham, I., Sargent, C. A., Trowsdale, J. & Campbell, R. D. Proc. natn. Acad. Sci. U.S.A. 84, 7237−7241 (1987). | ChemPort |
22.	Hill, A. V. S. et al. Nature 352, 595−600 (1991). | Article | PubMed | ISI | ChemPort |
23.	Hill, A. V. S. et al. Nature 360, 434−439 (1992). | Article | PubMed | ISI | ChemPort |
24.	Titus, R. G., Sherry, B. & Cerami, A. Parasitol. Today 12, A13−A16 (1991). | ChemPort |
25.	Wong, G. H. W., Kamb, A. & Goeddel, D. V. in Tumor Necrosis Factor. The Molecules and their Emerging Role in Medicine Vol. 1 (ed. Beutler, B.) 371−381 (Raven, New York, 1992).
26.	Grau, G. E., Parida, S. K., Pointaire, P., Barnes, P. F. & Modlin, R. L. in Tumour Necrosis Factor. The Molecules and their Emerging Role in Medicine Vol. 1 (ed. Beutler, B.) 329−340 (Raven, New York, 1992).
27.	Brewster, D. R., Kwiatkowski, D. & White, N. J. Lancet 336, 1039−1043 (1990). | Article | PubMed | ISI | ChemPort |
28.	Nedospasov, S. A. et al. Cold Spring Harb. Symp. quant. Biol. 51, 611−624 (1986). | PubMed | ISI | ChemPort |
29.	Hill, A. V. S. et al. Proc. natn. Acad. Sci. U.S.A. 89, 2277−2281 (1992). | ChemPort |
30.	Allsopp, C. E. M. et al. Hum. Immun. 30, 105−109 (1991). | PubMed | ChemPort |