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Letters to Nature
Nature 376, 246 - 249 (20 July 2002); doi:10.1038/376246a0

Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria

C. Ruwende*, S. C. Khooᤠ, R. W. Snowá¤, S. N. R. Yates*, D. Kwiatkowskiᤠá§, S. Gupta, P. Warnᤠá¤, C. E. M. Allsoppᤠ, S. C. Gilbert*, N. Peschuá¤, C. I. Newboldᤠ, B. M. Greenwoodá§, K. Marshᤠ& A. V. S. Hill*ᤠá¶

*The Wellcome Trust Centre for Human Genetics, University of Oxford, Windmill Road, Oxford 0X3 7BN, UK
ᤠInstitute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford 0X3 9DU, UK
á¤KEMRI Clinical Research Centre, Kilifi Unit, PO Box 230, Kilifi, Kenya
á§Medical Research Council Laboratories, Fajara, PO Box 273, Banjul, The Gambia
Department of Zoology, University of Oxford, Oxford 0X1 3PS, UK
á¶To whom correspondence should be addressed.

GLUCOSES-PHOSPHATE dehydrogeiiase (G6PD) deficiency, the most common enzymopathy of humans, affects over 400 million people1. The geographical correlation of its distribution with the historical endemicity of malaria suggests that this disorder has risen in frequency through natural selection by malaria2,3. However, attempts to confirm that G6PD deficiency is protective in case-control studies of malaria have yielded conflicting results4á¤-8. Hence, for this X-linked disorder, it is unclear whether both male hemizygotes and female heterozygotes are protected or, as frequently suggested, only females1,5á¤-11. Furthermore, how much protection may be afforded is unknown. Here we report that, in two large case-control studies of over 2,000 African children, the common African form of G6PD deficiency (G6PD Aá¤-) is associated with a 46á¤-58% reduction in risk of severe malaria for both female heterozygotes and male hemizygotes. A mathematical model incorporating the measured selective advantage against malaria suggests that a counterbalancing selective disadvantage, associated with this enzyme deficiency, has retarded its rise in frequency in malaria-endemic regions. Although G6PD deficiency is now regarded as a generally benign disorder, in earlier environmental conditions it could have been significantly disadvantageous.

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