Protective Effect of Mediterranean-type Glucose-6-phosphate Dehydrogenase Deficiency Against Malaria

Overview

Journal Elife

Specialty Biology

Date 2021 Feb 5

PMID 33543710

Citations 22

Authors

Ghulam R Awab

Fahima Aaram

Natsuda Jamornthanyawat

Kanokon Suwannasin

Watcharee Pagornrat

James A Watson

Charles J Woodrow

Arjen M Dondorp

Nicholas Pj Day

Mallika Imwong

Nicholas J White

Affiliations

Soon will be listed here.

Abstract

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) found across Europe and Asia is thought to confer protection against malaria, but its effect is unclear. We fitted a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients presenting with acute malaria and 1408 population controls. G6PD Med was associated with reductions in symptomatic malaria incidence of 76% (95% credible interval [CI], 58-88) in hemizygous males and homozygous females combined and 55% (95% CI, 38-68) in heterozygous females. Unless there is very large population stratification within the Pashtun (confounding these results), the G6PD Med genotype confers a very large and gene-dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by studies measuring G6PD deficiency prevalence in healthy subjects.

Citing Articles

Human immune system: Exploring diversity across individuals and populations.

Hoang Nguyen K, Le N, Nguyen P, Nguyen H, Hoang D, Huynh C Heliyon. 2025; 11(2):e41836.

PMID: 39911431 PMC: 11795082. DOI: 10.1016/j.heliyon.2025.e41836.

Revealing the secrets of Blue Zones.

Ulusu N Front Pharmacol. 2024; 15:1428111.

PMID: 39726786 PMC: 11669513. DOI: 10.3389/fphar.2024.1428111.

Linked-evidence modelling of qualitative G6PD testing to inform low- and intermediate-dose primaquine treatment for radical cure of Plasmodium vivax.

Gatton M PLoS Negl Trop Dis. 2024; 18(9):e0012486.

PMID: 39236082 PMC: 11407642. DOI: 10.1371/journal.pntd.0012486.

Glucose-6-phosphate Dehydrogenase Variants: Analysing in Indian Plasmodium vivax Patients.

Jakhan J, Foko L, Narang G, Singh V Acta Parasitol. 2024; 69(3):1522-1529.

PMID: 39164542 DOI: 10.1007/s11686-024-00883-2.

Implementation of Glucose-6-Phosphate Dehydrogenase (G6PD) testing for Plasmodium vivax case management, a mixed method study from Cambodia.

Cassidy-Seyoum S, Chheng K, Chanpheakdey P, Meershoek A, Hsiang M, von Seidlein L PLOS Glob Public Health. 2024; 4(7):e0003476.

PMID: 39028699 PMC: 11259306. DOI: 10.1371/journal.pgph.0003476.

References

Awab G, Imwong M, Bancone G, Jeeyapant A, Day N, White N . Chloroquine-Primaquine versus Chloroquine Alone to Treat Vivax Malaria in Afghanistan: An Open Randomized Superiority Trial. Am J Trop Med Hyg. 2017; 97(6):1782-1787. PMC: 5805052. DOI: 10.4269/ajtmh.17-0290. View

White N . Anaemia and malaria. Malar J. 2018; 17(1):371. PMC: 6194647. DOI: 10.1186/s12936-018-2509-9. View

Watson J, Leopold S, Simpson J, Day N, Dondorp A, White N . Collider bias and the apparent protective effect of glucose-6-phosphate dehydrogenase deficiency on cerebral malaria. Elife. 2019; 8. PMC: 6361583. DOI: 10.7554/eLife.43154. View

Luzzatto L, Arese P . Favism and Glucose-6-Phosphate Dehydrogenase Deficiency. N Engl J Med. 2018; 378(1):60-71. DOI: 10.1056/nejmra1708111. View

Bienzle U, Ayeni O, LUCAS A, Luzzatto L . Glucose-6-phosphate dehydrogenase and malaria. Greater resistance of females heterozygous for enzyme deficiency and of males with non-deficient variant. Lancet. 1972; 1(7742):107-10. DOI: 10.1016/s0140-6736(72)90676-9. View

Khim N, Benedet C, Kim S, Kheng S, Siv S, Leang R . G6PD deficiency in Plasmodium falciparum and Plasmodium vivax malaria-infected Cambodian patients. Malar J. 2013; 12:171. PMC: 3671135. DOI: 10.1186/1475-2875-12-171. View

Leslie T, Briceno M, Mayan I, Mohammed N, Klinkenberg E, Sibley C . The impact of phenotypic and genotypic G6PD deficiency on risk of plasmodium vivax infection: a case-control study amongst Afghan refugees in Pakistan. PLoS Med. 2010; 7(5):e1000283. PMC: 2876136. DOI: 10.1371/journal.pmed.1000283. View

Lopera-Mesa T, Doumbia S, Konate D, Anderson J, Doumbouya M, Keita A . Effect of red blood cell variants on childhood malaria in Mali: a prospective cohort study. Lancet Haematol. 2015; 2(4):e140-9. PMC: 4418020. DOI: 10.1016/S2352-3026(15)00043-5. View

Leopold S, Watson J, Jeeyapant A, Simpson J, Phu N, Hien T . Investigating causal pathways in severe falciparum malaria: A pooled retrospective analysis of clinical studies. PLoS Med. 2019; 16(8):e1002858. PMC: 6707545. DOI: 10.1371/journal.pmed.1002858. View

10.

Samilchuk E, Dsouza B, Al-Awadi S . Population study of common glucose-6-phosphate dehydrogenase mutations in Kuwait. Hum Hered. 1998; 49(1):41-4. DOI: 10.1159/000022838. View

11.

Beutler E . G6PD deficiency. Blood. 1994; 84(11):3613-36. View

12.

Uyoga S, Ndila C, Macharia A, Nyutu G, Shah S, Peshu N . Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in Kenya: a case-control and a cohort study. Lancet Haematol. 2015; 2(10):e437-44. PMC: 4703047. DOI: 10.1016/S2352-3026(15)00152-0. View

13.

Phyo A, Jittamala P, Nosten F, Pukrittayakamee S, Imwong M, White N . Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis. 2015; 16(1):61-69. PMC: 4700386. DOI: 10.1016/S1473-3099(15)00320-5. View

14.

Santana M, Monteiro W, Siqueira A, Costa M, Sampaio V, Lacerda M . Glucose-6-phosphate dehydrogenase deficient variants are associated with reduced susceptibility to malaria in the Brazilian Amazon. Trans R Soc Trop Med Hyg. 2013; 107(5):301-6. DOI: 10.1093/trstmh/trt015. View

15.

Ruwende C, Khoo S, Snow R, Yates S, Kwiatkowski D, Gupta S . Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature. 1995; 376(6537):246-9. DOI: 10.1038/376246a0. View

16.

Dewasurendra R, Rockett K, Fernando S, Carter R, Kwiatkowski D, Karunaweera N . G6PD gene variants and its association with malaria in a Sri Lankan population. Malar J. 2015; 14:93. PMC: 4343272. DOI: 10.1186/s12936-015-0603-9. View

17.

Yi H, Li H, Liang L, Wu Y, Zhang L, Qiu W . The glucose-6-phosphate dehydrogenase Mahidol variant protects against uncomplicated Plasmodium vivax infection and reduces disease severity in a Kachin population from northeast Myanmar. Infect Genet Evol. 2019; 75:103980. PMC: 6832843. DOI: 10.1016/j.meegid.2019.103980. View

18.

Mason P, Berrebi A, Al-Ali A, OPPENHEIM A, Luzzatto L . Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet. 1990; 47(6):1013-9. PMC: 1683892. View

19.

Louicharoen C, Patin E, Paul R, Nuchprayoon I, Witoonpanich B, Peerapittayamongkol C . Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians. Science. 2009; 326(5959):1546-9. DOI: 10.1126/science.1178849. View

20.

Jamornthanyawat N, Awab G, Tanomsing N, Pukrittayakamee S, Yamin F, Dondorp A . A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan. PLoS One. 2014; 9(2):e88605. PMC: 3931629. DOI: 10.1371/journal.pone.0088605. View