Endothelial Protein C Receptor Gene Variants Not Associated with Severe Malaria in Ghanaian Children

Abstract Background: Two recent reports have identified the Endothelial Protein CReceptor (EPCR) as a key molecule implicated in severe malaria pathology. First, itwas shown that EPCR in the human microvasculature mediates sequestration ofPlasmodium falciparum-infected erythrocytes. Second, microvascular thrombosis,one of the major processes causing cerebral malaria, was linked to a reduction inEPCR expression in cerebral endothelial layers. It was speculated that geneticvariation affecting EPCR functionality could influence susceptibility to severemalaria phenotypes, rendering PROCR, the gene encoding EPCR, a promisingcandidate for an association study.Methods: Here, we performed an association study including high-resolutionvariant discovery of rare and frequent genetic variants in the PROCR gene. Thestudy group, which previously has proven to be a valuable tool for studying thegenetics of malaria, comprised 1,905 severe malaria cases aged 1–156 monthsand 1,866 apparently healthy children aged 2–161 months from the Ashanti Regionin Ghana, West Africa, where malaria is highly endemic. Association of geneticvariation with severe malaria phenotypes was examined on the basis of singlevariants, reconstructed haplotypes, and rare variant analyses.Results: A total of 41 genetic variants were detected in regulatory and codingregions of PROCR, 17 of which were previously unknown genetic variants. Inassociation tests, none of the single variants, haplotypes or rare variants showedevidence for an association with severe malaria, cerebral malaria, or severe malariaanemia.