Abstract
X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) found across Europe and Asia is thought to confer protection against malaria, but its effect is unclear. We fitted a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients presenting with acute Plasmodium vivax malaria and 1408 population controls. G6PD Med was associated with reductions in symptomatic P. vivax malaria incidence of 76% (95% credible interval [CI], 58-88) in hemizygous males and homozygous females combined and 55% (95% CI, 38-68) in heterozygous females. Unless there is very large population stratification within the Pashtun (confounding these results), the G6PD Med genotype confers a very large and gene-dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by studies measuring G6PD deficiency prevalence in healthy subjects.
Highlights
In red blood cells, glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) is the only source of reduced nicotinamide adenine dinucleotide phosphate (NADPH) (Beutler, 1994; Luzzatto and Arese, 2018)
764 Pashtun patients presenting with acute vivax malaria (304 males, 460 females) and 699 Pashtun controls (342 males, 357 females) were studied; 236 healthy males came from the epidemiology study reported previously (Awab et al, 2017) and the remaining control subjects came from the same locations as the clinical malaria studies (Table 1; Figure 1)
Under the Bayesian model, assuming Hardy–Weinberg equilibrium, Turkmenistan these results suggest that G6PDd Med hemizygous males and homozygous females have 68% protection against acute P. vivax malaria, and G6PDd Med heterozygous females have 51% protection
Summary
Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) is the only source of reduced nicotinamide adenine dinucleotide phosphate (NADPH) (Beutler, 1994; Luzzatto and Arese, 2018). G6PD deficiency reflects instability, not absence, of this enzyme, which is essential for normal cellular function. As G6PD deficient red cells age, they become increasingly susceptible to oxidant haemolysis. G6PD deficiency is the most common enzyme abnormality in humans. It is found across the malaria-endemic world with mutant gene prevalences up to 35% (average 8–10%) (Howes et al, 2012). G6PD deficiency is X-linked, so males are either normal or fully deficient.
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