African Glucose-6-Phosphate Dehydrogenase Alleles Associated with Protection from Severe Malaria in Heterozygous Females in Tanzania

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. © 2015 manjurano et al.