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

MalariaGEN Consortium

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)e1004960
JournalPLoS Genetics
Volume11
Issue number2
DOIs
Publication statusPublished - 11 Feb 2015

Keywords

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

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