Abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as 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. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.
Highlights
Glucose-6-phosphate dehydrogenase (G6PD), encoded by the G6PD gene on chromosome X, is an enzyme that acts to control oxidative damage in red blood cells
In contrast to other malaria resistance loci such as sickle cell trait and blood group O, which show highly consistent and statistically significant effects across different locations in this large multi-centre study (Malaria Genomic Epidemiology Network, 2014), the observed associations with G6PD deficiency are at lower levels of statistical significance and vary between locations (Supplementary files 1D–J) (Manjurano et al, 2015; Uyoga et al, 2015; Shah et al, 2016)
This is partly because of the genetic complexity of G6PD deficiency, which is affected by multiple allelic variants and has different effects in males and females
Summary
Glucose-6-phosphate dehydrogenase (G6PD), encoded by the G6PD gene on chromosome X, is an enzyme that acts to control oxidative damage in red blood cells. The geographical distribution of G6PD deficiency corresponds to regions of the world where malaria is endemic, or has been in the relatively recent past, and it has been estimated that approximately 350 million people living in malaria-endemic countries are affected (Allison, 1960; Motulsky, 1960; Howes et al, 2012) It was proposed over half a century ago, and is widely accepted, that G6PD deficiency has risen to high frequency in malaria-endemic regions because it confers some level of resistance to malaria (Allison, 1960; Luzzatto, 2015). Other studies have indicated that the protective effect is present in both heterozygous females and hemizygous males (Ruwende et al, 1995; Clark et al, 2009; Shah et al, 2016) or that it is confined to hemizygous G6PD-deficient males (Guindo et al, 2007), or that there are no protective effects at all (Johnson et al, 2009; Toure et al, 2012)
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