Multi-centre analysis of the complex effects of G6PD deficiency on resistance to severe malaria

G6PD deficiency is believed to confer protection against Plasmodium falciparum malaria, but it has proved difficult to define the precise nature of the protective effect, since G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual’s level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. We construct models based on these findings to re-examine the hypothesis that G6PD polymorphism is maintained in human populations by balancing selection due to malaria.