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SCT is a heterozygous genetic condition resulting from a single point mutation in the gene for the beta chain of hemoglobin (hemoglobin S, HbS), by which an encoded glutamate at position six is replaced with valine [1,2]. The prevalence of hemoglobin S in regions where it provides protection against malaria is a textbook example of balanced polymorphism and natural selection. G6PD is an enzyme which catalyzes the first step of the pentose phosphate pathway and supports the production of reduced glutathione, a major defense against oxidant stress in red blood cells. G6PD deficiency is an X-linked condition associated with damage to red blood cells and hemolysis in response to a variety of exposures, including infection, ingestion of fava beans, or exposure to certain chemicals or medications [3,4]. A number of epidemiological studies have associated SCT or G6PD deficiency with protection against malaria, in particular severe, life-threatening malaria in its cerebral form [5–9]. Protection by SCT and G6PD deficiency are usually thought to act independently, but no studies have reported whether the protective effects of these two conditions are synergistic, are neutrally additive, or interfere with one another. Here we report on the occurrence of uncomplicated and severe malaria in Malian children with SCT, the G6PD (A−) polymorphism, or both of these conditions together. Among children with SCT, the prevalence of severe versus uncomplicated malaria in children with the G6PD (A−) polymorphism was 12.2%. When evaluated by sex, this prevalence was 6.6% and 28.5% in hemizygous males and heterozygous females, respectively. These results raise the possibility that the heterozygous G6PD (A−) condition and sickle trait do not supplement and may even interfere with one another in their protection against severe malaria (OR = 15; 95CI 2.07–132.31; P = 0.003). SCT and G6PD (A−) deficiency are frequently cited examples of red blood cell polymorphisms that confer resistance to malaria. Despite the different hemoglobin and enzyme functions that are affected, these polymorphisms are prevalent at comparably high frequencies in many populations of Mali and other regions of Africa [10,11]. These distributions are generally thought to reflect natural selection from the protections that SCT and G6PD (A−) deficiency independently provide against severe malaria [12,13]. Results of the work presented here confirm the association of SCT with protection against severe malaria (P = 0.01). This result corroborates with that of Doumbo et al. (1992) who reported on severe malaria children in a pediatric hospital of Mali. Another study likewise reported a protective effect of SCT against severe forms of malaria in the neighboring country of Burkina Faso [14]. Curiously, our study found that SCT provides significant protection against severe malaria in female but not male children of the villages of Kangaba and Kela (Table I). The reason for this differential signal of protection in the children is not known. Whether it may relate to additional sex-linked genetic factors or particular environmental conditions of the villages is a question that will require further investigation. Table I Distribution of Hemoglobin Types Among Uncomplicated and Severe Cases Malaria in Malian Children In a previous article, we reported that the hemizygous G6PD (A−) condition in the male children of Kangaba and Kela is associated with protection against severe malaria [9]. With this evidence in hand and also with evidence for a high degree of severe protection by SCT in female children, we tested whether an enhanced protective effect might be detected when the G6PD (A−) polymorphism and SCT were present in combination. In hemoglobin AS females heterozygous for G6PD (A−), the occurrence of severe malaria in four individuals suggested no synergistic or additive effect of the two conditions; instead, an OR of 15 (95%CI 2.07–132.31; P = 0.003) suggested the possibility of interference (negative epistasis) between G6PD (A−) heterozygosity and sickle trait in the female children (Table II). However, in sickle trait males with the hemizygous G6PD (A−) condition, no such evidence was found negative epistasis between sickle trait and G6PD (A−) heterozygosity (OR = 0.47; 95CI 0.07–2.40*; P = 0.53). This may reflect no interference due to an absence of a detectable protective activity from SCT in the male children of Kangaba and Kela (discussed above). However, considering the low numbers of severe malaria cases with both sickle trait and a G6PD (A−) condition in our study, additional studies with greater numbers of subjects will be required to further evaluate the possibilities suggested here. Table II Prevalence of G6PD Types in Malian Sickle Trait Children with Uncomplicated or Severe Malaria Our observations invite consideration of the molecular mechanisms by which various erythrocyte polymorphisms protect against severe malaria. A report from Kenya recently provided evidence for negative epistasis between SCT and alpha-thalassemia in protection against malaria [16]. How the protective mechanisms of these and other conditions including G6PD (A−) might interact to mutually interfere in malaria protection remains to be resolved. By the way, more recent study with a limited number of patients has shown that G6PD deficiency and SCT have no effect on the severity of anemia in children infected with both HIV-1 and P. falciparum [17] despite the high proportion of G6PD deficiency in coinfected children. Further study with large sample size is needed to confirm this observation. Understanding the interaction of malaria protective factors in various infectious diseases may be a valuable tool of medical interest. Our evaluation of data was previously collected in the villages of Kangaba and Kela, Mali [9]. Subjects in the case–control study included children 10 years or less of age who presented with clinical symptoms of malaria. Microscopic confirmations of parasitemia, assignments of the cases into uncomplicated or severe malaria, and hemoglobin typing and G6PD (A−) detection were as described [9]. Data evaluation and analysis were performed under consents and protocols approved by Institutional Review Boards of the National Institute of Allergy and Infectious Diseases, Bethesda, MD and of the University of Bamako, Mali.