Glucose-6-phosphate dehydrogenase deficiency and risk of malaria: systematic review and meta-analysis
Original Article

Glucose-6-phosphate dehydrogenase deficiency and risk of malaria: systematic review and meta-analysis

Shubhasmita Sahoo1 ORCID logo, Shashikant Swarnakar2 ORCID logo, Udit Narayan Padhi1 ORCID logo, Henu Kumar Verma3 ORCID logo, LVKS Bhaskar1 ORCID logo

1Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India; 2Department of Biochemistry, Chandulal Chandrakar Memorial Government Medical College, Durg, India; 3Department of Lung Health and Immunity, Helmholtz Zentrum Munich, Munich, Bayren, Germany

Contributions: (I) Conception and design: LVKS Bhaskar; (II) Administrative support: LVKS Bhaskar; (III) Provision of study materials or patients: S Sahoo; (IV) Collection and assembly of data: S Sahoo, UN Padhi; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: LVKS Bhaskar, D.Sc. Department of Zoology, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur-495009, Chhattisgarh, India. Email: lvksbhaskar@gmail.com.

Background: Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme expressed ubiquitously and catalyzes the initial step of the pentose phosphate pathway. G6PD deficiency adversely affects red blood cells (RBCs), leading to the most common inherited hematological disorder. The present study aims to assess the prevalence of G6PD deficiency among malaria-infected and healthy individuals.

Methods: Publications related to G6PD deficiency and malaria were searched through the databases. The prevalence of G6PD deficiency phenotype was assessed using the meta-analysis for Jamovi R (MAJOR) module from the Jamovi library. To estimate the pooled risk ratio (RR) of G6PD deficiency among patients with malaria, we utilized the Review Manager 5.4.1 software.

Results: A total of 33 datasets sourced from 27 studies were included in the present meta-analysis. The estimated average prevalence was found to be 11%. Analysis of RR indicated that the G6PD deficiency does not significantly differ between malaria patients and healthy individuals [RR =0.91, 95% confidence interval (CI): 0.76–1.10; P=0.35]. The study identified a high level of heterogeneity between studies (I2=72%). Stratified analysis reveals that the G6PD deficient allele is associated with protection against malaria, specifically when the infection is exclusively caused by P. falciparum (RR =0.77, 95% CI: 0.61–0.97; P=0.03) in populations where the prevalence of the G6PD deficient allele exceeds 13% (RR =0.72, 95% CI: 0.57–0.91; P=0.006).

Conclusions: As the independent studies included in this meta-analysis employ varied techniques for detecting malaria and G6PD deficiency, these results should be interpreted with caution, and further investigations are warranted.

Keywords: Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency); malaria; prevalence; meta-analysis

Received: 02 April 2025; Accepted: 25 September 2025; Published online: 31 October 2025.

doi: 10.21037/jlpm-25-13

Highlight box

Key findings

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency shows no overall significant association with malaria, but offers protection against P. falciparum in high-prevalence regions.

What is known and what is new?

• G6PD deficiency is the most common inherited blood disorder and affects red blood cell (RBC) stability.

• Its potential protective role against malaria, especially Plasmodium falciparum, has been suggested in past studies.

• Prevalence and effects of G6PD deficiency vary geographically and ethnically.

• This study found no significant overall association between G6PD deficiency and malaria infection.

• Stratified analysis reveals a protective effect against P. falciparum in populations where G6PD deficiency is more common (>13% prevalence).

• It highlights the importance of population-level genetic context and malaria species when evaluating G6PD’s role.

What is the implication, and what should change now?

• G6PD deficiency may offer protection against P. falciparum in high-prevalence regions.

• Future research and malaria control strategies should consider G6PD prevalence and malaria species in specific populations.

Introduction

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme expressed ubiquitously, possessing housekeeping properties. It plays a crucial role in maintaining the integrity and proper function of red blood cells (RBCs), and it is indispensable in glucose metabolism. G6PD catalyzes the initial step of the pentose phosphate pathway, converting glucose-6-phosphate to 6-phosphogluconolactone and generating nicotinamide adenine dinucleotide phosphate (NADPH) (1). NADPH serves as an electron donor, providing the reducing energy necessary for the regeneration of reduced glutathione. Consequently, NADPH sustains glutathione proteins and enzymes in their reduced state, safeguarding RBCs against oxidative damage (2). This mechanism represents the primary source of NADPH in erythrocytes (3). Therefore, G6PD deficiency adversely affects RBCs, leading to the most common inherited haematological disorder.

The gene encoding the G6PD enzyme is located on Xq28 and is inherited as an X-linked blood disorder. Numerous missense mutations in the G6PD gene have been documented to decrease the stability and activity of the enzyme. RBCs with reduced G6PD enzyme levels are susceptible to cell lysis following exposure to oxidative stress conditions (4). Due to this, RBCs infected by the malaria parasite are also destroyed by phagocytosis, thereby suppressing parasite growth within the RBC (5,6). Further, G6PD deficiency disrupts the oxidative stress in RBCs created by the infestation of malarial parasite, which makes the RBCs less hospitable to the parasite (7). Consequently, a direct correlation between P. falciparum malaria prevalence and the incidence of G6PD deficiency has been reported (8). Globally, approximately 400 million individuals are affected by G6PD deficiency disorder, with prevalence ranging from 8% to 30% in malaria-endemic regions (9). Furthermore, anti-malarial drugs such as the 8-aminoquinoline class (primaquine, tafenoquine), chloroquine (4-aminoquinoline), quinolones, chloramphenicol, sulfonamides, nitrofurantoin (antibiotics), dapsone, and phenazopyridine induce oxidative stress, which may not be adequately neutralized by G6PD-deficient RBCs, leading to hemolytic crises (10). However, primaquine and tafenoquine are the only anti-malarial drugs available to prevent the spread of P. vivax malaria, despite causing dangerous side effects in G6PD-deficient individuals (11). Consequently, mild or low dosages of primaquine or tafenoquine are prescribed for G6PD-deficient patients. Heterozygous G6PD-deficient females are more protected from malaria compared to G6PD-deficient hemizygous males or homozygous females, although this protection remains questionable (5). However, it’s important to note that the relationship between G6PD deficiency and malaria is influenced by various factors, including the specific genetic variants of G6PD, the prevalence of malaria transmission in a given population, and other genetic and environmental factors specific to the host. Therefore, the present study aims to assess the prevalence of G6PD deficiency among malaria-infected and healthy individuals using meta-analysis. We present this article in accordance with the PRISMA reporting checklist (available at https://jlpm.amegroups.org/article/view/10.21037/jlpm-25-13/rc) (6).

Methods

Study search and selection

Publications related to G6PD deficiency and malaria were systematically searched through the PubMed and Google Scholar databases. The search utilized keywords including G6PD, malaria, and prevalence of G6PD deficiency, covering papers published up to January 2024. Inclusion criteria were established for the selection of articles as follows: (I) original studies delineating the relationship between G6PD deficiency and malaria; (II) studies reporting G6PD prevalence; (III) inclusion of data on G6PD deficiency and the number of patients with malaria, as well as data on healthy individuals. Publications unrelated to G6PD deficiency and malaria were excluded. Two authors independently screened titles and abstracts of the retrieved papers and identified 27 relevant papers for further assessment. Data extraction encompassed the following information from all eligible studies: authors’ names, year of study, country, study design, prevalence of G6PD deficiency in malaria patients and healthy subjects (Table S1). The flow of the study selection process is illustrated in Figure 1.

Figure 1 PRISMA diagram showing the process of study retrieval for meta-analysis. G6PD, glucose-6-phosphate dehydrogenase.

Statistical analysis

The pooled prevalence of G6PD deficiency phenotype in both malaria patients and healthy subjects was assessed using the meta-analysis for Jamovi R (MAJOR) module from the Jamovi library. Heterogeneity between studies was measured using the I2 statistic. The Review Manager 5.4.1 software was employed to estimate the pooled risk ratio (RR) of having G6PD deficiency in patients with malaria. The random-effects model was utilized to pool the data. Publication bias was evaluated through visual inspection of the funnel plot.

Results

The present meta-analysis included 33 prevalence estimates to assess the prevalence of G6PD deficiency in both malaria and healthy individuals. The observed prevalence of G6PD deficiency ranged from 1% to 30%, mainly due to between-study variance (I2=72%). The estimated average prevalence was 11% [95% confidence interval (CI): 8–13%] (Figure 2). The individual RRs, along with the pooled RR, were illustrated in the forest plot (Figure 3). A RR of 0.91 with a 95% CI of 0.76–1.10 indicates that G6PD deficiency does not significantly differ between malaria patients and healthy individuals. Substantially high between-study heterogeneity observed in this study suggests potential variations among studies (I2=72%). Subgroup analysis based on the ethnicity, frequency of the G6PD allele and type of malaria parasite was conducted (Table 1, Figure S1). Subgroup analysis by ethnicity revealed that the RR of G6PD deficiency in patients with malaria compared to healthy individuals varied among Asian (RR =0.95, 95% CI: 0.66–1.38, P=0.80), African (RR =0.86, 95% CI: 0.68–1.07, P=0.18), and Caucasian (RR =1.50, 95% CI: 0.44–5.16, P=0.52) populations. This suggests that G6PD deficiency is not significantly associated with malaria in Asian, African, and Caucasian populations.

Figure 2 Forest plot showing average prevalence of G6PD deficiency in malaria patients. CI, confidence interval; G6PD, glucose-6-phosphate dehydrogenase.
Figure 3 Forest plot showing risk ratios of having G6PD deficiency in patients with & without malaria. CI, confidence interval; G6PD, glucose-6-phosphate dehydrogenase; M-H, Mantel-Haenszel.

Table 1

Subgroup analysis based on the ethnicity, frequency of the G6PD allele and type of malaria parasite

Subgroup No. of papers Heterogeneity Association
I2, % P value Risk ratio (95% CI) P value
Ethnicity
   Asia 13 79 <0.001 0.95 (0.66–1.38) 0.80
   Africa 18 69 <0.001 0.86 (0.68–1.07) 0.18
   Caucasian 2 0 0.46 1.50 (0.44–5.16) 0.52
Frequency of the G6PD deficient allele
   Frequency >13 12 73 <0.001 0.72 (0.57–0.91) 0.01
   Frequency ≤13 21 65 <0.001 1.13 (0.84–1.50) 0.42
Malaria parasite
   P. falciparum (alone) 14 69 <0.001 0.77 (0.61–0.97) 0.03
   P. falciparum and other strains 16 72 <0.001 1.20 (0.87–1.64) 0.26

CI, confidence interval; G6PD, glucose-6-phosphate dehydrogenase.

Stratification by G6PD deficiency allele prevalence revealed that protection against malaria was observed among studies with G6PD deficiency allele prevalence >13 (RR =0.72, 95% CI: 0.57–0.91, P=0.006), but not in studies with G6PD deficiency allele prevalence ≤13 (RR =1.33, 95% CI: 0.84–1.50, P=0.42) (Table 1, Figure S2). Additional stratification by single malaria parasite (P. falciparum) and mixed infections (P. falciparum with other species) revealed that protection against malaria was observed among studies where malaria was caused by P. falciparum only (RR =0.77, 95% CI: 0.61–0.97, P=0.03) (Table 1, Figure S3). However, the protective effect of the G6PD deficiency allele against malaria was not observed among studies where malaria was caused by mixed infections (RR =1.20, 95% CI: 0.87–1.64, P=0.26). The shape of the funnel plots did not reveal obvious asymmetry, indicating no evidence of major publication bias (Figure S4).

Discussion

In 1956, a group of researchers for the first time reported the deficiency of the G6PD enzyme in primaquine-sensitive erythrocytes (12). Subsequently, an increased frequency of G6PD deficiency was reported in malaria-endemic regions due to resistance to malaria (13). Furthermore, a 2–80 times greater infestation by malaria parasites was observed in G6PD nondeficient cells compared to deficient cells (14), indicating that G6PD-deficient cells provided protection against malaria. Although individuals with G6PD deficiency are mostly asymptomatic, acute hemolytic anemia may emerge when erythrocytes are exposed to drugs or infections, causing oxidative stress. However, the severity of hemolysis is primarily determined by the level of oxidative stress and the degree of enzymatic malfunction.

A plethora of previous studies have indicated that G6PD deficiency offers protection against malaria due to its hemolytic property (5,15-17). Therefore, G6PD deficiency is relatively frequent in malaria-endemic areas (18). In malaria-endemic areas of Eastern Indonesia, G6PD deficient subjects showed a lower risk of malaria than normal individuals (19). In females, G6PD deficiency is associated with P. falciparum infection, while in males, it is associated with P. vivax infection (19). In contrast to this, the malaria-endemic region in the Western Brazilian Amazon reported similar malaria episodes in both G6PD deficient and normal individuals, indicating that G6PD deficiency probably does not protect against P. vivax infection (20). Furthermore, P. vivax infestation was not significantly different between G6PD-deficient and G6PD-normal malaria patients in Ethiopia (21). In eastern Ethiopia, the prevalence of G6PD deficiency is low but correlated with a history of previous malaria infection (22). Although G6PD deficiency is uncommon among Bengalis of Bangladesh, patients with G6PD deficiency exhibited relatively substantially extended symptoms prior to admission compared to G6PD normal cases (23). Significantly lower malaria parasite infestation and less severe clinical symptoms were found in individuals with G6PD deficiency and sickle cell trait, compared to normal subjects (24). However, some studies reported that clinical complications such as anemia, jaundice, and blood transfusions were more frequent in G6PD deficient individuals than in normal individuals (20,25,26).

Some previous papers had reported that there is no association between G6PD deficiency and occurrence of uncomplicated P. falciparum malaria except for heterozygous girls (27). A previous meta-analysis demonstrated that G6PD deficiency can potentially protect against uncomplicated malaria in African countries (28). This study also showed that there was no link between G6PD deficiency and severe malaria or other malaria species (28). Another contemporary meta-analysis also supported the notion that G6PD deficiency offers protection against severe malaria (29).

The findings of the current meta-analysis indicate that G6PD deficiency is not associated with protection against malaria in the overall population, including Asian, African, and Caucasian groups. However, stratified analysis reveals that the G6PD deficient allele is associated with protection against malaria, specifically when the infection is exclusively caused by P. falciparum in populations where the prevalence of the G6PD deficient allele exceeds 13%. These results should be interpreted with caution due to variations in the detection techniques for malaria and G6PD deficiency among the independent studies included in this meta-analysis. Not all of the selected articles, as indicated in Table S1, employed genotyping to identify G6PD deficiency, which may contribute to the high variability observed between studies. For example, a study that assessed the phenotype using the CareStart® method reported a sensitivity of only 0.68. Other studies relied on the older fluorescence spot test method, which also exhibits low sensitivity. A sub-analysis stratifying by sex was not performed, which may constitute an important limitation for a condition that is transmitted through sex-linked inheritance. Other potential limitations are the inconsistent definition of G6PD deficiency between studies, as well as the allelic heterogeneity of the G6PD locus. Therefore, further investigations are warranted to furnish researchers with conclusive evidence regarding whether the G6PD deficient allele serves as a genetic predictor of milder malaria in different populations.

Conclusions

This meta-analysis indicates that the G6PD deficient allele is associated with protection against malaria, specifically when the infection is exclusively caused by P. falciparum in populations with G6PD deficient allele frequency is >13%. Given the methodological variations and high heterogeneity between studies included in this meta-analysis, further well-designed studies with a large sample size and reliable diagnostic and genotyping methods are needed to validate this study’s findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-13/rc

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-13/prf

Funding: This work was supported by DST-INSPIRE Fellowship to Ms. Shubhasmita Sahoo (No. IF200223) for pursuing PhD under the guidance of Prof. LVKS Bhaskar at GGV, Bilaspur.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-13/coif). H.K.V. serves as an unpaid editorial board member of Journal of Laboratory and Precision Medicine from April 2025 to March 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Jiang Z, Wang M, Nicolas M, et al. Glucose-6-Phosphate Dehydrogenases: The Hidden Players of Plant Physiology. Int J Mol Sci 2022;23:16128. [Crossref] [PubMed]
  2. Koju N, Qin ZH, Sheng R. Reduced nicotinamide adenine dinucleotide phosphate in redox balance and diseases: a friend or foe? Acta Pharmacol Sin 2022;43:1889-904. [Crossref] [PubMed]
  3. Meng Q, Zhang Y, Hao S, et al. Recent findings in the regulation of G6PD and its role in diseases. Front Pharmacol 2022;13:932154. [Crossref] [PubMed]
  4. Orrico F, Laurance S, Lopez AC, et al. Oxidative Stress in Healthy and Pathological Red Blood Cells. Biomolecules 2023;13:1262. [Crossref] [PubMed]
  5. Luzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Blood 2020;136:1225-40. [Crossref] [PubMed]
  6. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. [Crossref] [PubMed]
  7. Hwang S, Mruk K, Rahighi S, et al. Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator. Nat Commun 2018;9:4045. [Crossref] [PubMed]
  8. Mukherjee MB, Colah RB, Martin S, et al. Glucose-6-phosphate dehydrogenase (G6PD) deficiency among tribal populations of India - Country scenario. Indian J Med Res 2015;141:516-20. [Crossref] [PubMed]
  9. Atarihuana S, Gallardo-Condor J, López-Cortés A, et al. Genetic basis and spatial distribution of glucose-6-phosphate dehydrogenase deficiency in ecuadorian ethnic groups: a malaria perspective. Malar J 2023;22:283. [Crossref] [PubMed]
  10. Ley B, Luter N, Espino FE, et al. The challenges of introducing routine G6PD testing into radical cure: a workshop report. Malar J 2015;14:377. [Crossref] [PubMed]
  11. Chu CS, Bancone G, Nosten F, et al. Primaquine-induced haemolysis in females heterozygous for G6PD deficiency. Malar J 2018;17:101. [Crossref] [PubMed]
  12. Alving AS, Carson PE, Flanagan CL, et al. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 1956;124:484-5. [Crossref] [PubMed]
  13. Allison AC. Glucose-6-phosphate dehydrogenase deficiency in red blood cells of East Africans. Nature 1960;186:531-2. [Crossref] [PubMed]
  14. Rumaseb A, Marfurt J, Kho S, et al. A fluorometric assay to determine the protective effect of glucose-6-phosphate dehydrogenase (G6PD) against a Plasmodium spp. infection in females heterozygous for the G6PD gene: proof of concept in Plasmodium falciparum. BMC Res Notes 2022;15:76. [Crossref] [PubMed]
  15. Yi H, Jiang W, Yang F, et al. G6pd-Deficient Mice Are Protected From Experimental Cerebral Malaria and Liver Injury by Suppressing Proinflammatory Response in the Early Stage of Plasmodium berghei Infection. Front Immunol 2021;12:719189. [Crossref] [PubMed]
  16. Palasuwan D, Palasuwan A, Boonpeng K, et al. Impairment of Invasion and Maturation and Decreased Selectivity of Plasmodium falciparum in G6PD Viangchan and Mahidol Variants. J Infect Dis 2022;225:1238-47. [Crossref] [PubMed]
  17. Cappadoro M, Giribaldi G, O’Brien E, et al. Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood 1998;92:2527-34.
  18. Marasini B, Lal BK, Thapa S, et al. G6PD deficiency in malaria endemic areas of Nepal. Malar J 2020;19:287. [Crossref] [PubMed]
  19. Sulistyaningrum N, Arlinda D, Hutagalung J, et al. Prevalence of Glucose 6-Phosphate Dehydrogenase Variants in Malaria-Endemic Areas of South Central Timor, Eastern Indonesia. Am J Trop Med Hyg 2020;103:760-6. [Crossref] [PubMed]
  20. Dombrowski JG, Souza RM, Curry J, et al. G6PD deficiency alleles in a malaria-endemic region in the Western Brazilian Amazon. Malar J 2017;16:253. [Crossref] [PubMed]
  21. Lo E, Zhong D, Raya B, et al. Prevalence and distribution of G6PD deficiency: implication for the use of primaquine in malaria treatment in Ethiopia. Malar J 2019;18:340. [Crossref] [PubMed]
  22. Shenkutie TT, Nega D, Hailu A, et al. Prevalence of G6PD deficiency and distribution of its genetic variants among malaria-suspected patients visiting Metehara health centre, Eastern Ethiopia. Malar J 2022;21:260. [Crossref] [PubMed]
  23. Plewes K, Soontarawirat I, Ghose A, et al. Genotypic and phenotypic characterization of G6PD deficiency in Bengali adults with severe and uncomplicated malaria. Malar J 2017;16:134. [Crossref] [PubMed]
  24. Awah FM, Chukwuemeka G, Olalekan SI, et al. A possible protective role of glucose-6-phosphate dehydrogenase deficiency and sickle haemoglobin genes against severe malaria in Madonna University, Elele Community. Jounrla of Medicine and Medical Sciences 2012;3:375-81.
  25. Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician 2005;72:1277-82.
  26. Noor B, Iqbal H, Suliman M, et al. Evaluation of the Frequency of G6PD Deficiency by a G6PD Quantitative Method in Jaundiced Infants Visiting Dogar Central Kurram Hospital. Medtigo Journal of Medicine 2025. Doi: 10.63096/medtigo30623110.
  27. Uyoga S, Ndila CM, Macharia AW, et al. 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:e437-44. [Crossref] [PubMed]
  28. Mbanefo EC, Ahmed AM, Titouna A, et al. Association of glucose-6-phosphate dehydrogenase deficiency and malaria: a systematic review and meta-analysis. Sci Rep 2017;7:45963. [Crossref] [PubMed]
  29. Sun F, Zhang J, Pu Y. Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria: A meta-analysis and trial sequential analysis. AIP Conference Proceedings 2017;1890:040028.
doi: 10.21037/jlpm-25-13
Cite this article as: Sahoo S, Swarnakar S, Padhi UN, Verma HK, Bhaskar LVKS. Glucose-6-phosphate dehydrogenase deficiency and risk of malaria: systematic review and meta-analysis. J Lab Precis Med 2025;10:19.

Article Options

Download Citation

Share