Abstract
BackgroundClinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency.Methodology/Prinicipal FindingsWe compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, the predominant East African allele). Although roughly the same percentage of males were identified as deficient using enzyme activity (12%) and genotype (14%), nearly 30% of males who were enzymatically deficient were wild-type at G202A. The number of deficient females was three-fold higher with assessment by genotype (21%) compared to enzyme activity (7%). Heterozygous females accounted for the majority (46/54) of children with a mutant genotype but normal enzyme activity. G6PD deficiency, as determined by G6PD enzyme activity, conferred a 52% (relative risk [RR] 0.48, 95% CI 0.31–0.75) reduced risk of uncomplicated malaria in females. In contrast, when G6PD deficiency was defined based on genotype, the protective association for females was no longer seen (RR = 0.99, 95% CI 0.70–1.39). Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37–0.88 for females).Conclusions/SignificanceThis study underscores the impact that the method of identifying G6PD deficient individuals has upon association studies of G6PD deficiency and uncomplicated malaria. We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity. These observations may help to explain the discrepancy in some published association studies involving G6PD deficiency and uncomplicated malaria.
Highlights
Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the first step of the pentose phosphate pathway, which converts glucose into pentose sugars for glycolysis and other biological reactions
We found that glucose-6-phosphate dehydrogenase (G6PD) deficiency had no significant association with the incidence of uncomplicated malaria in males regardless of which assay was used
In females, when G6PD deficiency was defined by enzyme activity, deficiency was associated with a 52% reduced risk of uncomplicated malaria
Summary
Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the first step of the pentose phosphate pathway, which converts glucose into pentose sugars for glycolysis and other biological reactions. Deficiency in G6PD was first described in the 1950s as the cause of hemolysis in response to the antimalarial drug primaquine [2]. G6PD deficiency is the most common enzymopathy worldwide, affecting approximately 330 million people [3]. Deficiency is caused by mutations in the X-linked G6PD gene, in which more than 160 mutations have been identified [4,5]. Malaria has exerted a tremendous selective pressure on the human genome, with an estimated 300–660 million cases of P. Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency
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