NATURAL-SELECTION OF HEMIZYGOTES AND HETEROZYGOTES FOR G6PD DEFICIENCY IN AFRICA BY RESISTANCE TO SEVERE MALARIA

GLUCOSE-6-PHOSPHATE dehydrogenase (G6PD) deficiency, the most common e nzymopathy of humans, affects over 400 million people(1). The geograph ical correlation of its distribution with the historical endemicity of malaria suggests that this disorder has risen in frequency through na tural selection by malaria(2.3). However, attempts to confirm that G6P D deficiency is protective in case-control studies of malaria have yie lded conflicting results(4-8). Hence, for this X-linked disorder, it i s unclear whether both male hemizygotes and female heterozygotes are p rotected or, as frequently suggested, only females(1,5-11). Furthermor e, how much protection may be afforded is unknown. Here we report that , in two large case-control studies of over 2,000 African children, th e common African form of G6PD deficiency (G6PD A-) is associated with a 46-58% reduction in risk of severe malaria for both female heterozyg otes and male hemizygotes. A mathematical model incorporating the meas ured selective advantage against malaria suggests that a counterbalanc ing selective disadvantage, associated with this enzyme deficiency, ha s retarded its rise in frequency in malaria-endemic regions. Although G6PD deficiency is now regarded as a generally benign disorder, in ear lier environmental conditions it could have been significantly disadva ntageous.