Malaria and Alexander the Great: How important is family history?

Alexander the Great died from an acute febrile illness in 323 BC. Recent analyses have suggested several possible causes of his death and one among them is malaria. However, the analyses of Alexander's terminal illness have failed to consider his family history. Carriers of mutations for alpha and beta thalassemias, and glucose-6-phosphate dehydrogenase deficiency are protected against severe forms of malaria and their pattern of inheritance is well established. Alexander's father, Phillip II, was from Macedonia where selection pressure from malaria was strong. Accordingly, he likely possessed one or more of the protective genotypes. His mother Olympias, however, was a descendant of Doric migrants from the North and her ancestors resided subsequently for centuries in the mountainous Epirus where selection pressure of malaria was weak. Hence it is unlikely that she possessed one or more of the genotypes protective against malaria. Therefore, the relative risk of Alexander the Great being genetically more susceptible to and succumbing from malaria was greater than for his father and the Macedonian generals among whom he died.