Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Geraldine M Clarke Kirk Rockett Katja Kivinen Christina Hubbart Anna E Jeffreys Kate Rowlands Muminatou Jallow David J Conway Kalifa A Bojang Margaret Pinder Stanley Usen Fatoumatta Sisay-Joof Giorgio Sirugo Ousmane Toure Mahamadou A Thera Salimata Konate Sibiry Sissoko Amadou Niangaly Belco Poudiougou Valentina D Mangano Edith C Bougouma Sodiomon B Sirima David Modiano Lucas N Amenga-Etego Anita Ghansah Kwadwo A Koram Michael D Wilson Anthony Enimil Jennifer Evans Olukemi K Amodu Subulade Olaniyan Tobias Apinjoh Regina Mugri Andre Ndi Carolyne M Ndila Sophie Uyoga Alexander Macharia Norbert Peshu Thomas N Williams Alphaxard Manjurano Nuno Sepúlveda Taane G Clark Eleanor Riley Chris Drakeley Hugh Reyburn Vysaul Nyirongo David Kachala Malcolm Molyneux Sarah J Dunstan Nguyen Hoan Phu Nguyen Ngoc Quyen Cao Quang Thai Tran Tinh Hien Laurens Manning Moses Laman Peter Siba Harin Karunajeewa Steve Allen Angela Allen Timothy ME Davis Pascal Michon Ivo Mueller Síle F Molloy Susana Campino Angeliki Kerasidou Victoria J Cornelius Lee Hart Shivang S Shah Gavin Band Chris CA Spencer Tsiri Agbenyega Eric Achidi Ogobara K Doumbo Jeremy Farrar Kevin Marsh Terrie Taylor Dominic P Kwiatkowski MalariaGEN Consortium
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has 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.