ArticleThe Lancet. Haematology2018
Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.
Article in The Lancet. Haematology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 2 of them syntheses that pooled it.
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Who cites it
72 citing papers in PubMed, 2 syntheses or guidelines pooled it, 120 citations in OpenAlex.
- Improving reproducibility of Plasmodium falciparum culture: a large-language-model-driven literature review and a parasite growth variability assessment of donor red blood cells.Malaria journal · 2025Pooled it
- HMOX1 STR polymorphism and malaria: an analysis of a large clinical dataset.Malaria journal · 2022Pooled it
- High-throughput genotyping assays for identification of glycophorin B deletion variants in population studies.Experimental biology and medicine (Maywood, N.J.) · 2021Trial
- G6PD variants but not Filipino beta-thalassemia are associated with reduced risk of Plasmodium knowlesi infection in Sabah, Malaysia.Malaria journal · 2026Article
- African-specific genetic loci determine iron status and risk of severe malaria and bacteremia in African children.Nature communications · 2026Article
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- α-Thalassemia has no association with asymptomatic Plasmodium falciparum carriage in three ecological zones of Ghana.Scientific reports · 2026Article
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- Plasma membrane calcium ATPases and cerebellar pathology: what's the role in the ataxia?Biology direct · 2025Review
- Human genetic variations conferring resistance to malaria.Journal of translational medicine · 2025Review
- Risk factors associated with pain episodes among sickle cell patients that visited Mulago National Referral Hospital-Uganda.BMC health services research · 2025Article
- Relation Between the Dantu Blood Group Variant and Bacteremia in Kenyan Children: A Population-Based Case-Control Study.The Journal of infectious diseases · 2025Article
- Sickle Trait and Alpha Thalassemia Increase NOS-Dependent Vasodilation of Human Arteries Through Disruption of Endothelial Hemoglobin-eNOS Interactions.Circulation · 2025Article
- Fetal hemoglobin enables malaria parasite growth in sickle cells but augments production of transmission stage parasites.PloS one · 2025Article
- From Genome-wide Association Studies to Functional Variants: ARL14 Cis-regulatory Variants Are Associated With Severe Malaria.The Journal of infectious diseases · 2024Article
- A Whole-Genome Scan Revealed Genomic Features and Selection Footprints of Mengshan Cattle.Genes · 2024Article
- ApoE: A new piece to the severe malaria puzzle.Pediatric research · 2024Article
- A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis.Human genomics · 2024Article
- Review
- Basigin mediation of Plasmodium falciparum red blood cell invasion does not require its transmembrane domain or interaction with monocarboxylate transporter 1.PLoS pathogens · 2024Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 6 institutions in 3 countries.
Funding
Abstract
backgroundHuman genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms-many related to the structure or function of red blood cells-and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress.
methodsWe did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria.
findingsBetween June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11-0·20; p=2·61 × 10
interpretationBoth ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health.
fundingWellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative.
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