Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria
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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.
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This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on November 30 2020, follows.
Summary
The exact relationship between G6PD deficiency and malaria protection remains uncertain. This study provides evidence that the G6PD Med mutation (563 C>T) protects against clinical Plasmodium vivax disease. It uses a Bayesian statistical approach which specifically elucidates the particular protection which female heterozygotes versus male hemizygotes (or female homozygotes) for the Med mutation may experience. This is an important contribution to our understanding of the relationship between G6PD deficiency and P. vivax.
Overall, the reviewers were positive about the work and its potential, but have some clear concerns that will require additional data, analyses, and interpretation. Below are the main …
This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on November 30 2020, follows.
Summary
The exact relationship between G6PD deficiency and malaria protection remains uncertain. This study provides evidence that the G6PD Med mutation (563 C>T) protects against clinical Plasmodium vivax disease. It uses a Bayesian statistical approach which specifically elucidates the particular protection which female heterozygotes versus male hemizygotes (or female homozygotes) for the Med mutation may experience. This is an important contribution to our understanding of the relationship between G6PD deficiency and P. vivax.
Overall, the reviewers were positive about the work and its potential, but have some clear concerns that will require additional data, analyses, and interpretation. Below are the main points raised by the reviewers that would need to be addressed to for a revised manuscript.
Essential Revisions
The presence of mixed infections: although the work is focused on P. vivax, the majority (95%) of malaria in Afghanistan is caused by P. falciparum that means mixed species infections are likely high and P. falciparum infections may be obscuring P. vivax infections. It is not clear to what extent G6PD deficiency may impact the chance of being coinfected with both falciparum and vivax. Ideally, PCR verification of these samples would be performed to confirm the species for samples included in the analysis. Without this molecular data, the overall assessments of susceptibility to vivax malaria in association with G6PD Med is incomplete.
The analysis relies on a number of assumptions made about Pashtun population genetics (e.g. is it reasonable to assume the same frequency of the relevant mutation throughout all the tribes in the study, and should this be at Hardy Weinberg equilibrium?) and it is not clear to what extent these assumptions are justified since little evidence/support is provided. In particular, the assumptions about Hardy Weinberg equilibrium of G6PD Med within the Pashtun population need to be justified and supported since the analysis is highly reliant on this assumption.
The exclusion criteria does not appear to have been uniformly applied - in particular anemia was an exclusion criteria for only part of the data. This was not clear and may impact the overall significance of statistical results.
While the manuscript makes a number of conclusions about female homozygotes, these are not strongly supported by the evidence. In particular, the study is likely under-powered with regard to clinical associations among female homozygotes with G6PD Med, but this is not addressed and the stated conclusions are likely stronger than what can be supported by the data/analyses provided.
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