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

• Published in: eLife Vol. 6
• Main Authors: Clarke, Geraldine M, Rockett, Kirk, Kivinen, Katja, Hubbart, Christina, Jeffreys, Anna E, Rowlands, Kate, Jallow, Muminatou, Conway, David J, Bojang, Kalifa A, Pinder, Margaret, Usen, Stanley, Sisay-Joof, Fatoumatta, Sirugo, Giorgio, Toure, Ousmane, Thera, Mahamadou A, Konate, Salimata, Sissoko, Sibiry, Niangaly, Amadou, Poudiougou, Belco, Mangano, Valentina D, Bougouma, Edith C, Sirima, Sodiomon B, Modiano, David, Amenga-Etego, Lucas N, Ghansah, Anita, Koram, Kwadwo A, Wilson, Michael D, Enimil, Anthony, Evans, Jennifer, Amodu, Olukemi K, Olaniyan, Subulade, Apinjoh, Tobias, Mugri, Regina, Ndi, Andre, Ndila, Carolyne M, Uyoga, Sophie, Macharia, Alexander, Peshu, Norbert, Williams, Thomas N, Manjurano, Alphaxard, Sepúlveda, Nuno, Clark, Taane G, Riley, Eleanor, Drakeley, Chris, Reyburn, Hugh, Nyirongo, Vysaul, Kachala, David, Molyneux, Malcolm, Dunstan, Sarah J, Phu, Nguyen Hoan, Quyen, Nguyen Ngoc, Thai, Cao Quang, Hien, Tran Tinh, Manning, Laurens, Laman, Moses, Siba, Peter, Karunajeewa, Harin, Allen, Steve, Allen, Angela, Davis, Timothy Me, Michon, Pascal, Mueller, Ivo, Molloy, Síle F, Campino, Susana, Kerasidou, Angeliki, Cornelius, Victoria J, Hart, Lee, Shah, Shivang S, Band, Gavin, Spencer, Chris Ca, Agbenyega, Tsiri, Achidi, Eric, Doumbo, Ogobara K, Farrar, Jeremy, Marsh, Kevin, Taylor, Terrie, Kwiatkowski, Dominic P
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 09.01.2017; eLIFE; eLife Sciences Publications, Ltd
• Subjects: Alleles; Anemia; Anemia - epidemiology; Anemia - pathology; Case-Control Studies; Enzymes; Epidemiology; Epidemiology and Global Health; Fatalities; Females; G6PD deficiency; Gene polymorphism; genetic association; Genomics and Evolutionary Biology; Glucosephosphate dehydrogenase; Glucosephosphate Dehydrogenase - genetics; Glucosephosphate Dehydrogenase Deficiency - complications; Humans; Hypotheses; Infections; infectious disease; Laboratories; Malaria; Malaria, Cerebral - epidemiology; Malaria, Cerebral - pathology; Malaria, Falciparum - epidemiology; Malaria, Falciparum - pathology; Males; Malària; Medical research; Medicine; Molecular biology; Plasmodium falciparum; Population; Risk Assessment; selection; Teaching hospitals; Tropical diseases; global health; epidemiology; evolutionary biology; selection; infectious disease; genetic association; genomics; human; G6PD deficiency
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.15085

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against 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 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 infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.