Does α +-Thalassaemia Protect against Malaria?

E ver since Haldane proposed in 1949 that thalassaemia might protect individuals against the scourge of malaria [1], the challenge has been to provide supporting evidence—be it at the cellular, clinical, or epidemiological level. The general topic of human red cell polymorphisms and malarial protection has attracted enormous interest, largely because this subject provides the most compelling example of natural selection and, hence, " survival of the fi ttest " in humans. Sickle cell trait remains the paradigm of a red cell polymorphism that protects against malaria. Several lines of evidence, including plausible cellular mechanisms, confi rm that this haemoglobinopathy provides up to 90% protection against death due to malaria [2]. However, there are many gaps in our knowledge of whether other common red cell variants, notably thalassaemia, might protect against malaria and of the mechanism of such protection. Why has investigation of the interaction between thalassaemias and malaria remained inconclusive despite our best efforts? For β-thalassaemia, it is only in a limited part of West Africa that it continues to co-exist with malaria. Malaria has been eradicated from most other regions where β-thalassaemia is common. The fi ndings of Willcox et al. support a protective role for β-thalassaemia, in which heterozygotes one-to-four years old appear to have a reduced risk of malaria, using an arbitrary density criterion of 1 × 10 9 /l relative to controls (relative risk, 0.45; upper 95% confi dence interval, 0.79) [3]. By contrast, α +-thalassaemia (in which one or two of the four α-globin genes are deleted) is exceedingly common throughout sub-Saharan Africa, an area of high malarial transmission. However, thus far, the effects of α +-thalassaemia on the clinical manifestations of malaria in this area have not been extensively studied. And the few studies that have been carried out on the relationship between α +-thalassaemia and malaria have not provided an all-encompassing and plausible cellular mechanism for protection. Malarial parasites can certainly invade and multiply within α +-thalassaemic cells [4]. They also appear to cytoadhere equally well to endothelial cells as do parasitized normal red cells [5]. So how does thalassaemia protect against malaria? Carlson and colleagues proposed (with supporting evidence) that thalassaemic cells have a reduced ability to form rosettes (a process in which uninfected red cells bind to infected cells), which causes harm perhaps by aiding and abetting the obstruction of capillary blood fl ow and leading to sequestration of schizont-infected …