of similar hemosiderin deposits in the pancreas. Recently, Gordeuk et al. (18) demonstrated that the disease is genetic; however, unlike hereditary hemochromatosis of Caucasians, the disease is not linked to the HLA locus. In Southern Africa, the disease is associated with a high intake of beer brewed in steel drums, and it is proposed that the disease results from an interaction of genetic susceptibility and the intake of excessive iron and alcohol. Why would I speculate that the gene responsible for this disease was selected for by increased fitness in a malaria-endemic area? How could abnormalities in iron metabolism be involved in resistance to malaria when the parasite has a ready supply of iron from digestion of hemoglobin, a main source of amino acids for the parasite? Iron in the form of ferriprotoporphyrin IX is highly toxic to the parasite. The parasite detoxifies iron by forming malaria pigment, a form that is inaccessible to the parasite. Malaria pigment is β-hematin (19) that can be formed in the test tube from polymerization of ferriprotoporphyrin IX at pH 3 and high temperatures. In the cell, however, formation of β-hematin requires a polymerase, an enzymatic activity that was discovered by Slater and Cerami (20). Interestingly, polymerization is inhibited by chloroquine and other active 4-aminoquinolines (20), solving the mystery of the mode of chloroquine action. It has been further shown, through studies with iron chelation by desferroxamine, that the malaria parasite must obtain iron from the outside by unknown mechanisms (21). Iron uptake by the parasite may require a ferric reductase, a receptor, and a transporter molecule. If altered iron metabolism is proven to confer resistance to malaria, it would be an impetus to explore iron-related pathways in malaria therapy. In addition, this African disease may cause increased liver disease in African Americans. The study of these questions would require identification of the genetic basis of iron overload and the determination of whether this gene is associated with increased resistance to malaria in Africa and liver disease in African Americans. It is clear that hypertension and iron overload in Africans and African Americans may be preventable by diet, and the search for its genetic basis deserves high priority to develop molecular probes to identify those at risk.


Piazza et al. (22) were the first to present evidence of the association between HLA and malaria from gene frequencies in Sardinia, comparing lowland areas where malaria occurred and highland areas (22). In the definitive studies by Hill et al. (23), a class I molecule, HLA-B53, was found in lower frequency in Gambian children with severe malaria than in the general population. Class I molecules contain a groove that

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