title: 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: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.
authors: Alphaxard
authors: A
authors: Manjurano
authors: Department of Infection and Immunology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors: Nuno
authors: N
authors: Sepulveda
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.
authors: Behzad
authors: B
authors: Nadjm
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.
authors: George
authors: G
authors: Mtove
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.
authors: Hannah
authors: H
authors: Wangai
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.
authors: Caroline
authors: C
authors: Maxwell
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.
authors: Raimos
authors: R
authors: Olomi
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania; Department of Infection and Immunology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors: Hugh
authors: H
authors: Reyburn
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania; Department of Infection and Immunology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors: Eleanor M
authors: EM
authors: Riley
authors: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania; Department of Infection and Immunology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors: Christopher J
authors: CJ
authors: Drakeley
authors: Pathogen Molecular Biology Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors: Taane G
authors: TG
authors: Clark
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers; D005828:Genetics, Population; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008288:Malaria / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D008297:Male; D012641:Selection, Genetic; D013636:Tanzania
chemical_list: D005819:Genetic Markers; D005954:Glucosephosphate Dehydrogenase