The genetic risk of acute seizures in African children with falciparum malaria

Authors

  • Symon M. Kariuki,

    Corresponding author
    1. Kenya Medical Research Institute, Centre for Geographic Medicine Research Coast, Kilifi, Kenya
    2. Department of Psychiatry, University of Oxford, Oxford, United Kingdom
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  • Kirk Rockett,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
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  • Taane G. Clark,

    1. Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
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  • Hugh Reyburn,

    1. Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
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  • Tsiri Agbenyega,

    1. Department of Physiology, School of Medical Sciences, Kwame Nkurumah University of Science and Technology, Kumasi, Ghana
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  • Terrie E. Taylor,

    1. Department of Internal Medicine, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, U.S.A
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  • Gretchen L. Birbeck,

    1. International Neurologic and Psychiatric Epidemiology Program, Michigan State University, East Lansing, Michigan, U.S.A
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  • Thomas N. Williams,

    1. Kenya Medical Research Institute, Centre for Geographic Medicine Research Coast, Kilifi, Kenya
    2. Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
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  • Charles R. J. C. Newton

    1. Kenya Medical Research Institute, Centre for Geographic Medicine Research Coast, Kilifi, Kenya
    2. Department of Psychiatry, University of Oxford, Oxford, United Kingdom
    3. Neurosciences Unit, Institute of Child Health, University College London, London, United Kingdom
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Summary

Purpose

It is unclear why some children with falciparum malaria develop acute seizures and what determines the phenotype of seizures. We sought to determine if polymorphisms of malaria candidate genes are associated with acute seizures.

Methods

Logistic regression was used to investigate genetic associations with malaria-associated seizures (MAS) and complex MAS (repetitive, prolonged, or focal seizures) in four MalariaGEN African sites, namely: Blantyre, Malawi; Kilifi, Kenya; Kumasi, Ghana; and Muheza, Tanzania. The analysis was repeated for five inheritance models (dominant, heterozygous, recessive, additive, and general) and adjusted for potential confounders and multiple testing.

Key Findings

Complex phenotypes of seizures constituted 71% of all admissions with MAS across the sites. MAS were strongly associated with cluster of differentiation-ligand-rs3092945 in females in Kilifi (p = 0.00068) and interleukin (IL)-17 receptor E-rs708567 in the pooled analysis across the sites (p = 0.00709). Complex MAS were strongly associated with epidermal growth factor module-containing mucin-like hormone receptor (EMR)1-rs373533 in Kumasi (p = 0.00033), but none in the pooled analysis. Focal MAS were strongly associated with IL-20 receptor A-rs1555498 in Muheza (p = 0.00016), but none in the pooled analysis. Prolonged MAS were strongly associated with complement receptor 1-rs17047660 in Kilifi (p = 0.00121) and glucose-6-phosphate dehydrogenase-rs1050828 in females in the pooled analysis (p = 0.00155). Repetitive MAS were strongly associated with EMR1-rs373533 in Kumasi (p = 0.00003) and cystic fibrosis transmembrane conductance receptor-rs17140229 in the pooled analysis (p = 0.00543). MAS with coma/cerebral malaria were strongly associated with EMR1-rs373533 in Kumasi (p = 0.00019) and IL10-rs3024500 in the pooled analysis across the sites (p = 0.00064).

Significance

We have identified a number of genetic associations that may explain the risk of seizures in >2,000 cases admitted to hospitals with MAS across four sites in Africa. These associations differed according to phenotype of seizures and site.

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