Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has 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 of P. falciparum infection. 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 of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations. DOI: http://dx.doi.org/10.7554/eLife.15085.001

• Publication year

  2016

• Venue

  eLife

• Publication date

  2016-10-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.7554/eLife.15085PMID 28067620PMCID 5222559
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Management of relapsing Plasmodium vivax malaria

  2016cited by this paper
• Heterogeneous alleles comprising G6PD deficiency trait in West Africa exert contrasting effects on two major clinical presentations of severe malaria

  2016influential reference
• G6PD deficiency: a polymorphism balanced by heterozygote advantage against malaria.

  2015influential reference
• African Glucose-6-Phosphate Dehydrogenase Alleles Associated with Protection from Severe Malaria in Heterozygous Females in Tanzania

  2015cited by this paper
• A novel locus of resistance to severe malaria in a region of ancient balancing selection

  2015cited by this paper
• Reappraisal of known malaria resistance loci in a large multi-centre study

  2014influential reference
• A systematic analysis of global anemia burden from 1990 to 2010.

  2014cited by this paper
• Severe Malaria

  2014cited by this paper
• G6PD A- deficiency and severe malaria in The Gambia: heterozygote advantage and possible homozygote disadvantage.

  2014cited by this paper
• Improved whole-chromosome phasing for disease and population genetic studies

  2013cited by this paper
• G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map

  2012cited by this paper
• Candidate Polymorphisms and Severe Malaria in a Malian Population

  2012cited by this paper
• Glucose-6-phosphate dehydrogenase (G6PD) mutations database: review of the "old" and update of the new mutations.

  2012cited by this paper
• Supplementary Information for ‘ Improved whole chromosome phasing for disease and population genetic studies ’

  2012cited by this paper
• Candidate Human Genetic Polymorphisms and Severe Malaria in a Tanzanian Population

  2012cited by this paper
• Severe acquired anaemia in Africa: new concepts

  2011cited by this paper
• Population genetics of malaria resistance in humans

  2011influential reference
• A linear complexity phasing method for thousands of genomes

  2011cited by this paper
• Distinct clinical and immunologic profiles in severe malarial anemia and cerebral malaria in Zambia.

  2011influential reference
• Molecular Evolution of the Major Histocompatibility Complex

  2011cited by this paper
• Guidelines for the treatment of malaria

  2010cited by this paper
• Glucose-6-phosphate dehydrogenase deficiency and severe neonatal hyperbilirubinemia: a complexity of interactions between genes and environment.

  2010cited by this paper
• The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan

  2010cited by this paper
• Allelic heterogeneity of G6PD deficiency in West Africa and severe malaria susceptibility

  2009cited by this paper
• Impact of the Method of G6PD Deficiency Assessment on Genetic Association Studies of Malaria Susceptibility

  2009cited by this paper
• Maintenance or Loss of Genetic Variation Under Sexual and Parental Antagonism at a Sex-Linked Locus

  2009cited by this paper
• Positively Selected G6PD-Mahidol Mutation Reduces Plasmodium vivax Density in Southeast Asians

  2009cited by this paper
• Age patterns of severe paediatric malaria and their relationship to Plasmodium falciparum transmission intensity

  2009influential reference
• Glucose-6-phosphate dehydrogenase deficiency: a historical perspective.

  2008cited by this paper
• Glucose-6-phosphate dehydrogenase deficiency

  2008cited by this paper
• A global network for investigating the genomic epidemiology of malaria

  2008cited by this paper
• Testing for association on the X chromosome

  2008cited by this paper
• X-Linked G6PD Deficiency Protects Hemizygous Males but Not Heterozygous Females against Severe Malaria

  2007cited by this paper
• Anemia

  2007cited by this paper
• Present status of understanding on the G6PD deficiency and natural selection.

  2007cited by this paper
• Severe malaria in children in areas with low, moderate and high transmission intensity in Uganda

  2006influential reference
• Standardized data collection for multi-center clinical studies of severe malaria in African children: establishing the SMAC network.

  2006influential reference
• Severe Malaria

  2005cited by this paper
• Association of transmission intensity and age with clinical manifestations and case fatality of severe Plasmodium falciparum malaria.

  2005influential reference
• The Extent of Linkage Disequilibrium Caused by Selection on G6PD in Humans

  2005influential reference
• The treatment of complicated and severe malaria.

  2005influential reference
• Estimation of relative fitnesses from relative risk data and the predicted future of haemoglobin alleles S and C

  2003cited by this paper
• Nucleotide variability at G6pd and the signature of malarial selection in humans.

  2002cited by this paper
• Detecting recent positive selection in the human genome from haplotype structure

  2002cited by this paper
• Evidence for balancing selection from nucleotide sequence analyses of human G6PD.

  2002cited by this paper
• Hematologically important mutations: glucose-6-phosphate dehydrogenase.

  2002cited by this paper
• Haplotype Diversity and Linkage Disequilibrium at Human G6PD: Recent Origin of Alleles That Confer Malarial Resistance

  2001influential reference
• Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster.

  2000cited by this paper
• Malaria transmission and morbidity.

  1999influential reference
• Severe malaria in Burkina Faso: influence of age and transmission level on clinical presentation.

  1998influential reference
• Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment.

  1998cited by this paper
• Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa.

  1997cited by this paper
• Hematologically important mutations: glucose-6-phosphate dehydrogenase.

  1996influential reference
• Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria

  1995cited by this paper
• In-hospital morbidity and mortality due to malaria-associated severe anaemia in two areas of Malawi with different patterns of malaria infection.

  1994cited by this paper
• Severe childhood malaria in two areas of markedly different falciparum transmission in east Africa.

  1994influential reference
• Severe neonatal jaundice associated with glucose‐6‐phosphate dehydrogenase deficiency: pathogenesis and global epidemiology

  1994cited by this paper
• G6PD deficiency.

  1994cited by this paper
• HLA Associations with Malaria in Africa: Some Implications for MHC Evolution

  1991cited by this paper
• Metabolic polymorphisms and the role of infectious diseases in human evolution. 1960.

  1989cited by this paper
• Principles of population genetics (2nd edn)

  1989cited by this paper
• Severe falciparum malaria.

  1987cited by this paper
• Mortality and morbidity from malaria among children in a rural area of The Gambia, West Africa.

  1987cited by this paper
• The Duffy blood groups, vivax malaria, and malaria selection in human populations: a review.

  1984influential reference
• Principles of population genetics

  1981cited by this paper
• Letter: Temporary paralysis in childhood after influenza B.

  1975cited by this paper
• Glucose-6-phosphate dehydrogenase and malaria. Greater resistance of females heterozygous for enzyme deficiency and of males with non-deficient variant.

  1972influential reference
• Human glucose-6-phosphate dehydrogenase variants.

  1971cited by this paper
• Equilibria under natural selection at a sex-linked locus

  1964cited by this paper
• Metabolic polymorphisms and the role of infectious diseases in human evolution.

  1960cited by this paper
• Glucose-6-Phosphate Dehydrogenase Deficiency in Red Blood Cells of East Africans

  1960influential reference
• Genetic Equilibrium When More Than One Ecological Niche is Available

  1953influential reference
• Research Article (New England Journal of Medicine) Severe anemia in Malawian children

  year unknowncited by this paper

• Invasion and Development of Plasmodium falciparum in Erythroblasts of Humans Carrying G6PD Viangchan.

  2026cites this paper
• HbA1c underperforms in identifying abnormal glucose tolerance in the presence of G6PD deficiency: Insight from the Africans in America study

  2026cites this paper
• Global, regional, and national burden of glucose-6-phosphate dehydrogenase (G6PD) deficiency from 1990 to 2021: a systematic analysis of the global burden of disease study 2021

  2025cites this paper
• Severe malaria in Cameroon: a systematic review of a sticky problem and associated challenges to guide public health strategies in Africa

  2025cites this paper
• Human genetic variations conferring resistance to malaria

  2025cites this paper
• Prevalence of the Main Human Genetic Variants Related to Resistance to Malaria in a Population of the Colombian Pacific Coast

  2025cites this paper
• The global role of G6PD in infection and immunity

  2024cites this paper
• Relation Between the Dantu Blood Group Variant and Bacteremia in Kenyan Children: A Population-Based Case-Control Study

  2024cites this paper
• Adaptive admixture at ACKR1 (the Duffy locus) may have shaped Plasmodium vivax prevalence in Oman

  2024cites this paper
• ApoE: A new piece to the severe malaria puzzle

  2024cites this paper
• Severe haemolysis during primaquine radical cure of Plasmodium vivax malaria: two systematic reviews and individual patient data descriptive analyses

  2023cites this paper
• Malaria.

  2023cites this paper
• Severe Hemolysis during Primaquine Radical Cure of Plasmodium vivax Malaria: Two Systematic Reviews and Individual Patient Data Descriptive Analyses

  2023cites this paper
• The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study

  2023cites this paper
• Genome-wide association study identifies novel candidate malaria resistance genes in Cameroon

  2023cites this paper
• Genetic variants of TLR4, including the novel variant, rs5030719, and related genes are associated with susceptibility to clinical malaria in African children

  2023cites this paper
• A robust method for collider bias correction in conditional genome-wide association studies

  2022cites this paper
• A world free of malaria: It is time for Africa to actively champion and take leadership of elimination and eradication strategies

  2022cites this paper
• Influence of SERPINA1 Gene Polymorphisms on Anemia and Chronic Obstructive Pulmonary Disease

  2022cites this paper
• Controlled Human Malaria Infection reveals that the Dantu blood group variant provides high level protection against uncomplicated malaria

  2022cites this paper
• Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria

  2022cites this paper
• G6PD and HBB polymorphisms in the Senegalese population: prevalence, correlation with clinical malaria

  2022cites this paper
• An update on pharmacogenetic factors influencing the metabolism and toxicity of artemisinin-based combination therapy in the treatment of malaria

  2022cites this paper
• Association of TNF-Alpha, MBL2, NOS2, and G6PD with Malaria Outcomes in People in Southern Ghana

  2022influential citation
• Revisiting the malaria hypothesis: accounting for polygenicity and pleiotropy.

  2022cites this paper
• Impairment of Invasion and Maturation and Decreased Selectivity of Plasmodium falciparum in G6PD Viangchan and Mahidol Variants

  2021cites this paper
• Fine scale human genetic structure in three regions of Cameroon reveals episodic diversifying selection

  2021cites this paper
• Pharmacogenomics and COVID-19: clinical implications of human genome interactions with repurposed drugs

  2021cites this paper
• Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria

  2021cites this paper
• G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials

  2021influential citation
• Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision

  2021cites this paper
• Glucose-6-phosphate dehydrogenase activity in individuals with and without malaria: Analysis of clinical trial, cross-sectional and case–control data from Bangladesh

  2021cites this paper
• Glucose 6-Phosphate Dehydrogenase Deficiency

  2021cites this paper
• Transcriptome-Wide Association Study of Blood Cell Traits in African Ancestry and Hispanic/Latino Populations

  2021cites this paper
• Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision.

  2021cites this paper
• G6pd-Deficient Mice Are Protected From Experimental Cerebral Malaria and Liver Injury by Suppressing Proinflammatory Response in the Early Stage of Plasmodium berghei Infection

  2021cites this paper
• Genotypic glucose-6-phosphate dehydrogenase (G6PD) deficiency protects against Plasmodium falciparum infection in individuals living in Ghana

  2021cites this paper
• G6PD and HBB polymorphisms in Senegalese population: prevalence and correlations with clinical malaria

  2020cites this paper
• Evaluating the promise of inclusion of African ancestry populations in genomics

  2020cites this paper
• Assessment of protective relationship of G6PD and other lifestyle factors with Malaria: A case-control study of medical professionals from a teaching medical institute, Gujarat

  2020cites this paper
• Risk of pneumococcal bacteremia in Kenyan children with glucose-6-phosphate dehydrogenase deficiency

  2020cites this paper
• Common host variation drives malaria parasite fitness in healthy human red cells

  2020cites this paper
• Slope-Hunter: A robust method for index-event bias correction in genome-wide association studies of subsequent traits

  2020cites this paper
• Important Pharmacogenetic Information for Drugs Prescribed During the SARS‐CoV‐2 Infection (COVID‐19)

  2020cites this paper
• Strong gene dose dependent protective effect of Mediterranean type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria

  2020cites this paper
• Malaria parasite fitness in healthy human red cells is driven by common host variation

  2020cites this paper
• High-throughput genotyping assays for identification of glycophorin B deletion variants in population studies

  2020cites this paper
• A novel G6PD deleterious variant identified in three families with severe glucose-6-phosphate dehydrogenase deficiency

  2020cites this paper
• Evidence of positively selected G6PD A‐ allele reduces risk of Plasmodium falciparum infection in African population on Bioko Island

  2019cites this paper
• Prospects of genetic testing for steroid-resistant nephrotic syndrome in Nigerian children: a narrative review of challenges and opportunities

  2019cites this paper
• Plasmodium malariae and Plasmodium ovale infections and their association with common red blood cell polymorphisms in a highly endemic area of Uganda.

  2019cites this paper
• Bead-based assays to simultaneously detect multiple human inherited blood disorders associated with malaria

  2019cites this paper
• Associations between erythrocyte polymorphisms and risks of uncomplicated and severe malaria in Ugandan children: A case control study

  2018cites this paper
• Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

  2018cites this paper
• Medical genetics and genomic medicine in Nigeria

  2018cites this paper
• Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

  2018cites this paper
• Understanding human genetic factors influencing primaquine safety and efficacy to guide primaquine roll-out in a pre-elimination setting in southern Africa

  2018cites this paper
• Primaquine ineligibility in anti-relapse therapy of Plasmodium vivax malaria: the problem of G6PD deficiency and cytochrome P-450 2D6 polymorphisms

  2018cites this paper
• Human Genetic Factors and Resistance to Malaria

  2018cites this paper
• Glucose-6-phosphate dehydrogenase deficiency allelic variants and their prevalence in malaria patients in Eritrea

  2018cites this paper
• Role of the Swain-Langley and McCoy polymorphisms in complement receptor 1 in cerebral malaria

  2018cites this paper
• Point-of-Care Testing for G6PD Deficiency: Opportunities for Screening

  2018cites this paper
• Collider bias and the apparent protective effect of glucose-6-phosphate dehydrogenase deficiency on cerebral malaria

  2018influential citation
• Addressing the gender-knowledge gap in glucose-6-phosphate dehydrogenase deficiency: challenges and opportunities

  2018cites this paper
• Low and heterogeneous prevalence of glucose-6-phosphate dehydrogenase deficiency in different settings in Ethiopia using phenotyping and genotyping approaches

  2018cites this paper
• Edinburgh Research Explorer Two Complement Receptor One alleles have opposing associations with cerebral malaria and interact with +thalassaemia.

  2018cites this paper
• Two Complement Receptor One alleles have opposing associations with 1 cerebral malaria and interact with α + thalassaemia . 2 3

  2018cites this paper
• Prevalence, genetic variants and clinical implications of G-6-PD deficiency in Burkina Faso: a systematic review

  2017influential citation
• ADDIS ABABA UNIVERSITY SCHOOL OF GRADUATE STUDIES COLLEGE OF MEDICINE AND HEALTH SCIENCES DEPARTMENT OF MEDICAL BIOCHEMISTRY The prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency among Apparently Healthy Individuals in Selected Malaria Endemic Areas from Different Agroecological Zones of Et

  2017cites this paper
• Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda

  2017influential citation
• The role of the red blood cell in host defence against falciparum malaria: an expanding repertoire of evolutionary alterations

  2017cites this paper
• Mutations in the tetramer interface of human glucose‐6‐phosphate dehydrogenase reveals kinetic differences between oligomeric states

  2017cites this paper
• Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches

  2017cites this paper
• Ankyrin-1 Gene Exhibits Allelic Heterogeneity in Conferring Protection Against Malaria

  2017cites this paper
• G6PD deficiency alleles in a malaria-endemic region in the Western Brazilian Amazon

  2017cites this paper
• Evaluating the Causal Link Between Malaria Infection and Endemic Burkitt Lymphoma in Northern Uganda: A Mendelian Randomization Study

  2017cites this paper
• Genotypic and phenotypic characterization of G6PD deficiency in Bengali adults with severe and uncomplicated malaria

  2017cites this paper
• Glucose-6-Phosphate Dehydrogenase Deficiency.

  1995cites this paper
• Collider bias and the apparent 1 protective effect of 2 glucose-6-phosphate dehydrogenase 3 deficiency on cerebral malaria 4

  year unknowncites this paper