African glucose-6-phosphate dehydrogenase alleles associated with protection from severe malaria in heterozygous females in Tanzania.

Abstract

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.

• Authors: Alphaxard Manjurano, Nuno Sepulveda, Behzad Nadjm, George Mtove, Hannah Wangai, Caroline Maxwell, Raimos Olomi, Hugh Reyburn, Eleanor M Riley, Christopher J Drakeley, Taane G Clark, MalariaGEN Consortium
• Journal: PLoS genetics (PLoS Genet) Vol. 11 Issue 2 Pg. e1004960 (Feb 2015) ISSN: 1553-7404 [Electronic] United States
• PMID: 25671784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Genetic Markers
• Glucosephosphate Dehydrogenase

Topics

• Alleles
• Child
• Child, Preschool
• Chromosomes, Human, X
• Female
• Gene Frequency (genetics)
• Genetic Markers
• Genetics, Population
• Glucosephosphate Dehydrogenase (genetics)
• Haplotypes
• Heterozygote
• Humans
• Infant
• Malaria (genetics, parasitology, pathology)
• Male
• Selection, Genetic
• Tanzania