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Apolipoprotein-E4: risk of severe malaria and mortality and cognitive impairment in pediatric cerebral malaria

Pediatric Research (2023)Cite this article

Abstract

Background

The relationship of apolipoprotein-E4 (APOE4) to mortality and cognition after severe malaria in children is unknown.

Methods

APOE genotyping was performed in children with cerebral malaria (CM, n = 261), severe malarial anemia (SMA, n = 224) and community children (CC, n = 213). Cognition was assessed over 2-year follow-up.

Results

A greater proportion of children with CM or SMA than CC had APOE4 (n = 162, 31.0%; n = 142, 31.7%; n = 103, 24.2%, respectively, p = 0.02), but no difference was seen in APOE3 (n = 310, 59.4%; n = 267, 59.6%; n = 282, 66.2%, respectively, p = 0.06), or APOE2 (n = 50, 9.6%; n = 39, 8.7%; and n = 41, 9.6%, respectively, p = 0.87). APOE4 was associated with increased mortality in CM (odds ratio, 2.28; 95% CI, 1.01, 5.11). However, APOE4 was associated with better long-term cognition (ß, 0.55; 95% CI, 0.04, 1.07, p = 0.04) and attention (ß 0.78; 95% CI, 0.26, 1.30, p = 0.004) in children with CM < 5 years old, but worse attention (ß, −0.90; 95% CI, −1.69, −0.10, p = 0.03) in children with CM ≥ 5 years old. Among children with CM, risk of post-discharge malaria was increased with APOE4 and decreased with APOE3.

Conclusions

APOE4 is associated with higher risk of CM or SMA and mortality in children with CM, but better long-term cognition in CM survivors <5 years of age.

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Fig. 1: Flowchart describing the study participants at enrollment and follow-up in the three study groups.
Fig. 2: Risk of post-discharge clinical malaria according to APOE allele in children with cerebral malaria (n = 227) or severe malarial anemia (n = 221).
Fig. 3: Association of APOE4 allele with cognitive outcomes in children with cerebral malaria or severe malarial anemia over a 24-month follow-up period.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the children and their parents who participated in the study, and the study team for their dedicated effort in treating the children and collecting the data.

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke and the Fogarty International Center (grants R01NS055349, D43 NS078280 and D43TW010928). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding source had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Author information

Author notes

  1. These authors contributed equally: Giselle Lima-Cooper, Benson J. Ouma.

Authors and Affiliations

  1. Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Giselle Lima-Cooper, Dibyadyuti Datta, Caitlin Bond, Alejandro A. Soto, Andrea L. Conroy & Chandy C. John

  2. Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda

    Benson J. Ouma & Moses L. Joloba

  3. Office of the Vice President for Research, University of Minnesota, Minneapolis, MN, USA

    Gregory S. Park

  4. Department of Psychiatry, College of Health Sciences, Makerere University, Kampala, Uganda

    Paul Bangirana

  5. Department of Pediatrics and Child Health, Makerere University, Kampala, Uganda

    Robert O. Opoka & Richard Idro

  6. Nuffield Department of Medicine, Centre of Tropical Medicine and Global Health, University of Oxford, Oxford, UK

    Richard Idro

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Contributions

G.L.C. and B.J.O. performed the sample testing, data analysis and interpretation, and writing of the first draft of the manuscript; D.D. performed data analysis and interpretation and writing of the manuscript; C.B. performed data analysis and interpretation and writing of the manuscript; A.A.S. assisted in sample testing, data analysis and interpretation, and manuscript review; A.L.C. assisted in data interpretation and manuscript review; P.B. contributed to the study design, data collection and interpretation, and manuscript review; G.S.P. contributed to sample testing, data interpretation, and manuscript review; R.O.O. contributed to the study design, data collection and interpretation, and manuscript review; R.I. contributed to the study design, data collection and interpretation, and manuscript review; M.L.J. contributed to data analysis and interpretation, and manuscript review; C.C.J. designed the primary study and contributed to data collection, analysis, and interpretation and writing of the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Chandy C. John.

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The authors declare no competing interests.

Ethics approval and consent to participate

Ethical approval for the study was obtained from Makerere University School of Medicine Research and Ethics Committee, the Institutional Review Board at the University of Minnesota, and the Uganda National Council for Science and Technology. Written informed consent was obtained from parents or guardians of study participants and assent from children aged 7 years and above.

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Lima-Cooper, G., Ouma, B.J., Datta, D. et al. Apolipoprotein-E4: risk of severe malaria and mortality and cognitive impairment in pediatric cerebral malaria. Pediatr Res (2023). https://doi.org/10.1038/s41390-023-02912-8

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  • DOI: https://doi.org/10.1038/s41390-023-02912-8

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