title: Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.
abstract: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection againstPlasmodium falciparummalaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome ofP. falciparuminfection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes ofP. falciparuminfection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|MRC Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Geraldine M
authors.identifier: 0000-0001-7249-0289
authors.initials: GM
authors.lastname: Clarke
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|MRC Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom.|The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Kirk
authors.identifier: 0000-0002-6369-9299
authors.initials: K
authors.lastname: Rockett
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Katja
authors.initials: K
authors.lastname: Kivinen
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Hubbart
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Jeffreys
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Rowlands
authors.affiliation: Medical Research Council Unit The Gambia, Fajara, Gambia.|Edward Francis Small Teaching Hospital, Independence Drive, Banjul, Gambia.
authors.forename: Muminatou
authors.initials: M
authors.lastname: Jallow
authors.affiliation: Medical Research Council Unit The Gambia, Fajara, Gambia.|Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
authors.affiliation: Medical Research Council Unit The Gambia, Fajara, Gambia.
authors.forename: Kalifa A
authors.initials: KA
authors.lastname: Bojang
authors.affiliation: Medical Research Council Unit The Gambia, Fajara, Gambia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.affiliation: Medical Research Council Unit The Gambia, Fajara, Gambia.
authors.forename: Stanley
authors.initials: S
authors.lastname: Usen
authors.affiliation: Medical Research Council Unit The Gambia, Fajara, Gambia.
authors.forename: Fatoumatta
authors.initials: F
authors.lastname: Sisay-Joof
authors.affiliation: Medical Research Council Unit The Gambia, Fajara, Gambia.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.affiliation: Malaria Research and Training Centre, University of Bamako, Bamako, Mali.
authors.forename: Ousmane
authors.initials: O
authors.lastname: Toure
authors.affiliation: Malaria Research and Training Centre, University of Bamako, Bamako, Mali.
authors.forename: Mahamadou A
authors.identifier: 0000-0002-2679-035X
authors.initials: MA
authors.lastname: Thera
authors.affiliation: Malaria Research and Training Centre, University of Bamako, Bamako, Mali.
authors.forename: Salimata
authors.initials: S
authors.lastname: Konate
authors.affiliation: Malaria Research and Training Centre, University of Bamako, Bamako, Mali.
authors.forename: Sibiry
authors.initials: S
authors.lastname: Sissoko
authors.affiliation: Malaria Research and Training Centre, University of Bamako, Bamako, Mali.
authors.forename: Amadou
authors.initials: A
authors.lastname: Niangaly
authors.affiliation: Malaria Research and Training Centre, University of Bamako, Bamako, Mali.
authors.forename: Belco
authors.initials: B
authors.lastname: Poudiougou
authors.affiliation: University of Rome La Sapienza, Rome, Italy.
authors.forename: Valentina D
authors.initials: VD
authors.lastname: Mangano
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso.
authors.forename: Edith C
authors.initials: EC
authors.lastname: Bougouma
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso.
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.affiliation: University of Rome La Sapienza, Rome, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Modiano
authors.affiliation: Navrongo Health Research Centre, Navrongo, Ghana.
authors.forename: Lucas N
authors.initials: LN
authors.lastname: Amenga-Etego
authors.affiliation: Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
authors.forename: Anita
authors.initials: A
authors.lastname: Ghansah
authors.affiliation: Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
authors.forename: Kwadwo A
authors.initials: KA
authors.lastname: Koram
authors.affiliation: Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wilson
authors.affiliation: Komfo Anoyke Teaching Hospital, Kumasi, Ghana.
authors.forename: Anthony
authors.initials: A
authors.lastname: Enimil
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.|Kumasi Centre for Collaborative Research, Kumasi, Ghana.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Evans
authors.affiliation: University of Ibadan, Ibadan, Nigeria.
authors.forename: Olukemi K
authors.initials: OK
authors.lastname: Amodu
authors.affiliation: University of Ibadan, Ibadan, Nigeria.
authors.forename: Subulade
authors.initials: S
authors.lastname: Olaniyan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Buea, Buea, Cameroon.
authors.forename: Tobias
authors.initials: T
authors.lastname: Apinjoh
authors.affiliation: Department of Medical Laboratory Sciences, University of Buea, Buea, Cameroon.
authors.forename: Regina
authors.initials: R
authors.lastname: Mugri
authors.affiliation: Department of Medical Laboratory Sciences, University of Buea, Buea, Cameroon.
authors.forename: Andre
authors.initials: A
authors.lastname: Ndi
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
authors.forename: Carolyne M
authors.initials: CM
authors.lastname: Ndila
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
authors.forename: Sophie
authors.initials: S
authors.lastname: Uyoga
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
authors.forename: Alexander
authors.initials: A
authors.lastname: Macharia
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.|Department of Medicine, Faculty of Medicine, Imperial College, London, United Kingdom.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.affiliation: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.|Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Alphaxard
authors.initials: A
authors.lastname: Manjurano
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Nuno
authors.initials: N
authors.lastname: Sepúlveda
authors.affiliation: Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Taane G
authors.identifier: 0000-0001-8985-9265
authors.initials: TG
authors.lastname: Clark
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Riley
authors.affiliation: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.|Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Drakeley
authors.affiliation: Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi, Tanzania.|Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Hugh
authors.initials: H
authors.lastname: Reyburn
authors.affiliation: Malawi-Liverpool Wellcome Trust Clinical Research Programme, University of Malawi, Blantyre, Malawi.
authors.forename: Vysaul
authors.initials: V
authors.lastname: Nyirongo
authors.affiliation: Oxford University Clinical Research Unit, University of Oxford, Ho Chi Minh City, Vietnam.
authors.forename: David
authors.initials: D
authors.lastname: Kachala
authors.affiliation: Malawi-Liverpool Wellcome Trust Clinical Research Programme, University of Malawi, Blantyre, Malawi.|Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Molyneux
authors.affiliation: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Dunstan
authors.affiliation: Oxford University Clinical Research Unit, University of Oxford, Ho Chi Minh City, Vietnam.|Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam.
authors.forename: Nguyen Hoan
authors.initials: NH
authors.lastname: Phu
authors.affiliation: Oxford University Clinical Research Unit, University of Oxford, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Ngoc
authors.initials: NN
authors.lastname: Quyen
authors.affiliation: Oxford University Clinical Research Unit, University of Oxford, Ho Chi Minh City, Vietnam.|Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam.
authors.forename: Cao Quang
authors.initials: CQ
authors.lastname: Thai
authors.affiliation: Oxford University Clinical Research Unit, University of Oxford, Ho Chi Minh City, Vietnam.|Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam.|Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.
authors.forename: Laurens
authors.initials: L
authors.lastname: Manning
authors.affiliation: Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.
authors.forename: Moses
authors.initials: M
authors.lastname: Laman
authors.affiliation: Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.
authors.forename: Peter
authors.initials: P
authors.lastname: Siba
authors.affiliation: University of Western Australia, Perth, Australia.
authors.forename: Harin
authors.initials: H
authors.lastname: Karunajeewa
authors.affiliation: Swansea University, Swansea, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Allen
authors.affiliation: Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Allen
authors.affiliation: University of Western Australia, Perth, Australia.
authors.forename: Timothy Me
authors.initials: TM
authors.lastname: Davis
authors.affiliation: Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.|Faculty of Medicine and Health Sciences, Divine Word University, Madang, Papua New Guinea.
authors.forename: Pascal
authors.initials: P
authors.lastname: Michon
authors.affiliation: Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.|Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Barcelona Centre for International Health Research, Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Síle F
authors.initials: SF
authors.lastname: Molloy
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Nuffield Department of Population Health, The Ethox Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Kerasidou
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|MRC Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Cornelius
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Hart
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Shivang S
authors.initials: SS
authors.lastname: Shah
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|MRC Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Band
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Chris Ca
authors.initials: CC
authors.lastname: Spencer
authors.affiliation: Komfo Anoyke Teaching Hospital, Kumasi, Ghana.|Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: Tsiri
authors.initials: T
authors.lastname: Agbenyega
authors.affiliation: Department of Medical Laboratory Sciences, University of Buea, Buea, Cameroon.
authors.forename: Eric
authors.initials: E
authors.lastname: Achidi
authors.affiliation: Malaria Research and Training Centre, University of Bamako, Bamako, Mali.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Oxford University Clinical Research Unit, University of Oxford, Ho Chi Minh City, Vietnam.|Nuffield Department of Clinical Medicine, Center for Tropical Medicine, Oxford University, Oxford, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Blantyre Malaria Project at the College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Terrie
authors.initials: T
authors.lastname: Taylor
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|MRC Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom.|The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
mesh_terms: D000483:Alleles; D000740:Anemia / Q000453:epidemiology* / Q000473:pathology; D016022:Case-Control Studies; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000150:complications*; D006801:Humans; D016779:Malaria, Cerebral / Q000453:epidemiology* / Q000473:pathology; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000473:pathology; D018570:Risk Assessment
chemical_list: D005954:Glucosephosphate Dehydrogenase
keywords: G6PD deficiency; epidemiology; evolutionary biology; genetic association; genomics; global health; human; infectious disease; selection