%0 Journal Article
%T African Glucose-6-Phosphate Dehydrogenase Alleles Associated with Protection from Severe Malaria in Heterozygous Females in Tanzania
%A Alphaxard Manjurano
%A Behzad Nadjm
%A Caroline Maxwell
%A Christopher J. Drakeley
%A Eleanor M. Riley
%A George Mtove
%A Hannah Wangai
%A Hugh Reyburn
%A MalariaGEN Consortium
%A Nuno Sepulveda
%A Raimos Olomi
%A Taane G. Clark
%J -
%D 2015
%R 10.1371/journal.pgen.1004960
%X X-linked Glucose-6-phosphate dehydrogenase (G6PD) A- deficiency is prevalent in sub-Saharan Africa populations, and has been associated with protection from severe malaria. Whether females and/or males are protected by G6PD deficiency is uncertain, due in part to G6PD and malaria phenotypic complexity and misclassification. Almost all large association studies have genotyped a limited number of G6PD SNPs (e.g. G6PD202 / G6PD376), and this approach has been too blunt to capture the complete epidemiological picture. Here we have identified 68 G6PD polymorphisms and analysed 29 of these (i.e. those with a minor allele frequency greater than 1%) in 983 severe malaria cases and controls in Tanzania. We establish, across a number of SNPs including G6PD376, that only female heterozygotes are protected from severe malaria. Haplotype analysis reveals the G6PD locus to be under balancing selection, suggesting a mechanism of protection relying on alleles at modest frequency and avoiding fixation, where protection provided by G6PD deficiency against severe malaria is offset by increased risk of life-threatening complications. Our study also demonstrates that the much-needed large-scale studies of severe malaria and G6PD enzymatic function across African populations require the identification and analysis of the full repertoire of G6PD genetic markers
%K Malaria
%K Glucose-6-phosphate dehydrogenase deficiency
%K Haplotypes
%K Genetic loci
%K Alleles
%K Variant genotypes
%K Genetic epidemiology
%K Population genetics
%U https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004960