Cellular Mechanism by Which Genetic Variations in Human ATP2B4 Gene Protect Against Severe Malaria

Background: Recent genome-wide association and cross-sectional studies have identified novel human genetic polymorphisms associated with alterations in severe malaria risk. Some of the strongest associations have been identified in the ATP2B4 gene. ATP2B4 codes for PMCA4b, the primary regulator of erythrocyte calcium concentration. Methods: To investigate the cellular mechanisms by which polymorphisms in ATP2B4 alter malaria pathogenesis, we performed in vitro assays that model malaria pathogenesis on red blood cells (RBCs) collected from individuals (n=96) with and without copies of ATP2B4 variant haplotype. Findings: We found reduced rates of PMCA4b expression (p<0.0001), calcium expulsion (p<0.0001) and Plasmodium falciparum growth in RBCs from homozygote carriers of the mutant haplotype (p<0.01). We were unable to detect any difference in adhesion or var-gene expression in malaria infected RBCs with and without the variant ATP2B4 haplotype. Interpretation: This data is consistent with the conclusion that polymorphisms in ATP2B4, protect against severe falciparum malaria by controlling parasite density rather than adhesion and invasion. Funding: This work was supported by the Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine (MRCG at LSHTM) PhD fellowship. We acknowledge core funding to the MRC International Nutrition Group through MCA760-5QX00 from the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement. Declaration of Interest: None to declare. Ethical Approval: The study proposal was reviewed and approved by the Scientific Coordinating Committee of the Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine (MRCG at LSHTM) and ethical approval was granted by the Joint Gambia Government/Medical Research Council Ethics committee (SCC number 1421).