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
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
MRC Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom.
Elife. 2017 Jan 9;6:e15085. 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.
葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症被认为可提供针对疟疾的保护作用，但由于G6PD缺乏症具有多种等位基因变体，在男性和女性中具有不同影响，并且对感染的临床结果具有异质性影响，因此这种保护作用的确切性质难以界定。在此，我们报告了一项针对严重疟疾的大型多中心病例对照研究中G6PD缺乏症多种等位基因形式的分析，使用世界卫生组织（WHO）的G6PD突变分类方法，根据个体基因型估计其酶活性水平。汇总所有基因型后，我们发现G6PD缺乏程度的增加与脑型疟疾风险降低相关，但与严重疟疾贫血风险增加相关。基于这些发现的平衡选择模型表明，感染不同临床结果之间的进化权衡可能是人类群体中G6PD多态性水平高的主要原因。
