Journal
PLOS GENETICS
Volume 11, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004960
Keywords
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Funding
- Medical Research Council UK [G9901439, MR/K000551/1]
- MalariaGEN Project
- Wellcome Trust [WT077383/Z/05/Z, 090770/Z/09/Z, 090532/Z/09/Z, 077012/Z/05/Z]
- Foundation for the National Institutes of Health as part of the Bill & Melinda Gates' Grand Challenges in Global Health Initiative [566]
- Medical Research Council [G0600718, G0600230]
- Medical Research Council [G0600230, MR/K000551/1, MR/M006212/1, G0600718] Funding Source: researchfish
- MRC [G0600718, MR/M006212/1, MR/K000551/1, G0600230] Funding Source: UKRI
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X-linked Glucose-6-phosphate dehydrogenase (G6PD) A-deficiency is prevalent in sub-Saharan Africa populations, and has been associated with protection from severe malaria. Whether females and/or males are protected by G6PD deficiency is uncertain, due in part to G6PD and malaria phenotypic complexity and misclassification. Almost all large association studies have genotyped a limited number of G6PD SNPs (e.g. G6PD202 / G6PD376), and this approach has been too blunt to capture the complete epidemiological picture. Here we have identified 68 G6PD polymorphisms and analysed 29 of these (i.e. those with a minor allele frequency greater than 1%) in 983 severe malaria cases and controls in Tanzania. We establish, across a number of SNPs including G6PD376, that only female heterozy-gotes are protected from severe malaria. Haplotype analysis reveals the G6PD locus to be under balancing selection, suggesting a mechanism of protection relying on alleles at modest frequency and avoiding fixation, where protection provided by G6PD deficiency against severe malaria is offset by increased risk of life-threatening complications. Our study also demonstrates that the much-needed large-scale studies of severe malaria and G6PD enzymatic function across African populations require the identification and analysis of the full repertoire of G6PD genetic markers.
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