The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria 1 . In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and α + -thalassemia, a condition characterized by reduced production of the normal α-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria 2-4 , but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying α + -thalassemia. Negative epistasis could explain the failure of α + -thalassemia to reach fixation in any population in subSaharan Africa.The mutation underlying the hemoglobin S variant (HbS) is a prototypical example of a balanced polymorphism: its frequency in populations is determined both by positive selection for heterozygosity (HbAS) 5 and negative selection for homozygosity (HbSS), which causes sickle cell disease, a debilitating condition associated with chronic anemia and premature death. Negative selection has not been shown to affect the frequency of α + -thalassemias. Perhaps as a consequence, these conditions approach fixation in a number of populations; for unknown reasons, however, frequencies remain relatively low in much of sub-Saharan Africa 1 .Despite conclusive evidence that both HbAS and α + -thalassemia protect against severe and fatal P. falciparum malaria 2-4 , the mechanisms underlying this protection are poorly 6,7 , and parasite-infected HbAS erythrocytes also seem to be targeted for premature destruction by the spleen 6,8,9 . These hypothetical mechanisms are supported by both the reduced incidence of clinical malaria and the lower parasite densities observed in children with HbAS erythrocytes when they suffer from clinical attacks 3,10 . Much less is known about α + -thalassemia. Although both heterozygosity (-α/αα) and homozygosity (-α/-α) with respect to the underlying mutation protect against severe and fatal malaria 2,4 , neither protects against uncomplicated malaria 11 or affects parasite densities during incident episodes 2,12 . We believe that a better understanding of how these conditions protect against malaria might provide insights into both the pathophysiology of severe malaria and the hostparasite relationship more generally 10 . Accordingly, we studied the effects of both HbAS and α + -thalassemia on the epidemiology of malaria in children living on the coast of Kenya.We measured the incidence of P. falciparum malaria in two cohorts of children from Kilifi District, where al...

Although the ␣ ؉ thalassemias almost certainly confer protection against death from malaria, this has not been formally documented. We have conducted a study involving 655 case patients with rigorously defined severe malaria and 648 controls, frequency matched on area of residence and ethnic group. The prevalence of both heterozygous and homozygous ␣ ؉ thalassemia was reduced in both case patients with severe malaria (ad-