Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria

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% 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.

Genotypic glucose-6-phosphate dehydrogenase (G6PD) deficiency protects against Plasmodium falciparum infection in individuals living in Ghana

“…The hypnozoites of P. ovale and P. vivax are responsible for the relapse of malaria infection months after complete treatment [ 59 , 60 ]. Primaquine (PQ) is the recommended antimalarial used for clearing these hypnozoites, however, PQ may cause haemolysis in G6PD deficient individuals [ 9 , 61 , 62 ]. Although some studies have reported the association between G6PDd A- variants and protection against P. vivax malaria [ 60 – 63 ].…”

“…The protection offered by G6PDd A- against malaria infection is not well understood. It is unclear however, if both hemizygotes (A-) and heterozygotes (AA-) offer protection against severe malaria or bias towards females [ 9 , 22 ]. Although a recent case-control study conducted in Africa has reported a 46–58% reduced risk in severe malaria by both hemizygotes and heterozygotes G6PDd A- [ 23 ] and heterozygotes G6PDd A- but not hemizygotes G6PDd A- has been reported to protect against acute malaria among children in Nigeria, suggesting sex-specific malaria protection [ 24 , 25 ].…”

The global burden of Plasmodium vivax malaria is obscure and insidious

“…G6PDd is among the inherited blood disorders believed to have been selected by survival advantages against endemic malaria [ 54 – 57 , 103 , 104 ]. As already explained, P .…”

Taking on Plasmodium vivax malaria: A timely and important challenge

“…G6PD testing has not been made widely available and so the possibility of doing harm by causing oxidant haemolysis has markedly limited implementation of radical cure [11,12]. Individual and population risks associated with primaquine radical cure have not been defined well, particularly as G6PD deficiency protects against P. vivax malaria [13], nor has the cumulative adverse impact of not providing radical cure (i.e., the burden of relapse). However, mainly because of tafenoquine, more than a decade of recent development has resulted recently in marketing of the first point-of-care biosensors, which allow a quantitative measurement of G6PD activity [14][15][16].…”