X-Linked G6PD Deficiency Protects Hemizygous Males but Not Heterozygous Females against Severe Malaria

Background: Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A− form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. Methods and Findings: We conducted large case-control studies of the A− form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. Conclusions: The A− form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these conclusions are consistent with data from at least one previous study, they have not heretofore been realized to our knowledge, and they therefore give fresh perspectives on malaria protection by G6PD deficiency as an X-linked trait. In two populations in rural Mali, West Africa, G6PD A- deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria. Background.: “Favism” is a condition that results from a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD), and this disorder is thought to be the commonest enzyme-deficiency disease worldwide. The disease is named favism after the Italian word for broad beans (fava), which cause a classic reaction when eaten by people with G6PD deficiency. The G6PD enzyme is particularly important in red blood cells, where it protects against damage that can be caused by certain drugs or other stresses. There are a number of normal variants of G6PD, with G6PD A and G6PD B being common in Africa. However, abnormal mutations in the gene can lead to anemia as a result of the red blood cells breaking down in response to certain drugs or types of food, or in other situations. G6PD deficiency is not spread evenly around the world; it is particularly common in Africa and the Mediterranean, and up to 20%–25% of people in certain African regions can have the condition. Although there can be serious clinical outcomes from G6PD deficiency that result from the red blood cells being broken down, G6PD deficiency may protect against malaria. Why Was This Study Done?: The researchers here wanted to find out whether, in regions where virtually all children get malaria during early childhood, a mutation in G6PD A (written as G6PD A−) that leads to G6PD deficiency protects children from having their malaria episodes worsen into severe, life-threatening disease. They also wanted to look at whether the degree of protection from G6PD A− deficiency differed between boys and girls. The reason for looking at this had to do with the genetics of G6PD deficiency. The gene coding for G6PD is carried on the X chromosome, of which males have only one copy, whereas females have two. Therefore, males will be G6PD deficient when they inherit only one mutant gene, but females need to inherit two abnormal genes (or have the normal gene turned off, which happens by a process known as X-inactivation in a proportion of female cells). What Did the Researchers Do and Find?: This study was carried out in two regions of Mali, West Africa, where malaria affects virtually all children under the age of 5 years. The children recruited at each study site came from two distinct cultural groups, the Dogon people of Bandiagara and the Malinké people of Kangaba and Kela. The researchers studied children coming to the medical clinics in each area with either uncomplicated malaria (i.e., mild symptoms) or severe malaria. All patients were treated normally according to the standard practices for this region. Blood samples were collected from each child in order to see how many malaria parasites were in the blood, as well as to analyze each patient's DNA to work out whether they had a mutant form of the G6PD*A gene that causes the G6PD A− form of deficiency. What Do These Findings Mean?: These data show that the mutation in G6PD*A that leads to the G6PD A− deficiency gives children substantial protection against severe malaria, but this protection seems to be the case for boys and not girls who have only one mutant copy of the gene. There seems to be around a two-thirds drop in risk of severe malaria in boys with G6PD deficiency as compared to normal boys. At present the reason for this difference in protection is not clear, because it is not known how malaria parasites are affected by red blood cells that lack G6PD activity. Additional Information.: Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040066.