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

Date Published: March 13, 2007

Publisher: Public Library of Science

Author(s): Aldiouma Guindo, Rick M Fairhurst, Ogobara K Doumbo, Thomas E Wellems, Dapa A Diallo, Sanjeev Krishna

Abstract: BackgroundGlucose-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 FindingsWe 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.ConclusionsThe 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.

Partial Text: Glucose-6-phosphate dehydrogenase (G6PD) is important in the generation of reduced glutathione, a product key in the control of oxidative damage in erythrocytes. Although complete loss of this enzyme is presumably lethal, mutant forms of G6PD with partially deficient activity are common and have been associated with protection against malaria. Geographic distribution of these G6PD variants correlates with historic distributions of the disease [1,2], and a mutant allele (A−) encoding G6PD with 10%–50% of normal enzyme activity is widespread in Africa [3–5]. However, conclusions from case-control studies [5–7] and in vitro parasite culture experiments [8–10] have been conflicting and have not been reconciled satisfactorily with the differential expression of G6PD*A− in males and females. For example, studies using parasite densities but not clinical findings as indicators of disease severity suggested resistance in heterozygous females only, whereas hemizygous males paradoxically showed higher parasitemias despite more severe enzyme deficiency [7]. A report of near-equivalent protection against life-threatening malaria in both males and females [5] has also been difficult to reconcile with the differential expression of G6PD deficiency between the sexes, as hemizygous males would be expected to show an advantage over heterozygous females under at least one mechanism of protection currently advocated [11].

Among all children presenting to our clinics with fever and other symptoms of illness, our clinical and laboratory determinations identified 3,197 with uncomplicated (n = 2,765) or severe (n = 432) forms of malaria. Two observations indicated the populations of children in the clinics were representative of the populations at large. First, in Kela, the one village in our program small enough to realistically include children from all families, all but 112 of 1,288 age-eligible children in the population (∼50% of the cases in the Malinké-predominant group of Table 1) were seen for malaria and enrolled in our case-control study. From village census information, we located the 112 children, met with their families, and learned that reasons they had not come to the clinic for malaria treatment were various, including that they received other sources of care for uncomplicated malaria (e.g., family self treatment or seeing a local pharmacist), or that the children might have had malaria without sufficiently intense symptoms to seek care (e.g., reduced symptoms in some cases because of the presence of sickle trait) (unpublished data). These 112 children showed proportions of G6PD*A− alleles in males and females (7/58 = 12.1% and 8/54 = 14.8%, respectively) that did not differ significantly from those in the uncomplicated malaria groups (152/1,078 = 14.1% and 188/1,199 = 15.7%; Fisher’s exact test p-values 0.85 and 1.00, respectively). Second, in the larger village of Bandiagara contributing to the Dogon study group, we showed that the prevalence of Hb C in uncomplicated malaria patients was the same as that in more than 7,000 individuals from the overall population [13], a finding consistent with universal experience of Dogon children with parasitization and malaria. Since the malaria cases from that study also provided test samples for our present report, the observed prevalence of G6PD A− in our uncomplicated malaria control group likely reflects the prevalence of G6PD A− in the Dogon population at large.

In rural villages of Mali, where virtually all young children experience episodes of malaria, protective hemoglobinopathies and erythrocyte polymorphisms offer a tremendous survival benefit when they prevent progression of uncomplicated malaria to severe, life-threatening disease. Our study was designed to test for protection by the A− form of G6PD deficiency and determine whether the effect of this sex-linked polymorphism would be more evident in male or female children. Since children who never contract malaria are rare at our study sites, we used case-control comparisons of severe malaria patient “cases” against uncomplicated malaria patient “controls” as described by Hayes et al. [20] for epidemiological assessments of protection.



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