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

Abstract

BackgroundTwo recent reports have identified the Endothelial Protein C Receptor (EPCR) as a key molecule implicated in severe malaria pathology. First, it was shown that EPCR in the human microvasculature mediates sequestration of Plasmodium falciparum-infected erythrocytes. Second, microvascular thrombosis, one of the major processes causing cerebral malaria, was linked to a reduction in EPCR expression in cerebral endothelial layers. It was speculated that genetic variation affecting EPCR functionality could influence susceptibility to severe malaria phenotypes, rendering PROCR, the gene encoding EPCR, a promising candidate for an association study.MethodsHere, we performed an association study including high-resolution variant discovery of rare and frequent genetic variants in the PROCR gene. The study group, which previously has proven to be a valuable tool for studying the genetics of malaria, comprised 1,905 severe malaria cases aged 1–156 months and 1,866 apparently healthy children aged 2–161 months from the Ashanti Region in Ghana, West Africa, where malaria is highly endemic. Association of genetic variation with severe malaria phenotypes was examined on the basis of single variants, reconstructed haplotypes, and rare variant analyses.ResultsA total of 41 genetic variants were detected in regulatory and coding regions of PROCR, 17 of which were previously unknown genetic variants. In association tests, none of the single variants, haplotypes or rare variants showed evidence for an association with severe malaria, cerebral malaria, or severe malaria anemia.ConclusionHere we present the first analysis of genetic variation in the PROCR gene in the context of severe malaria in African subjects and show that genetic variation in the PROCR gene in our study population does not influence susceptibility to major severe malaria phenotypes.

Triggering receptor expressed on myeloid cells 1 (TREM‐1) and cytokine gene variants in complicated and uncomplicated malaria

“…This vicious cycle, involving reducing the interaction between mEPCR and PC to promote pro‐inflammatory cytokine production, may aggravate the severity of malaria. At the genetic level, no association between any of the genotypes and disease phenotype was observed (Table ), confirming earlier studies .…”

Emerging roles for hemostatic dysfunction in malaria pathogenesis

“…For example, a large Ghanaian association study failed to link EPCR H3 haplotype with malaria disease severity. 104 In contrast, a recent Thai study found that elevated sEPCR plasma levels in individuals with H3 haplotype were associated with protection from CM. 105 Evidently, larger studies are required to unequivocally determine whether EPCR haplotype and constitutively high sEPCR plasma concentration truly have an effect on malaria disease severity.…”

A meta-analysis of the endothelial protein C receptor rs867186 genotype in malaria

“…1). Five studies, published from 2014 to 2016, were eligible for meta-analysis [1,2,[24][25][26]. A total of 2995 SM, 487 uncomplicated malaria, and 2105 healthy controls from Thailand, Uganda, Benin, Tanzania, and Ghana were enrolled.…”

“…The abundance of the transcripts increased with malaria severity; however, each subtype transcript did not vary remarkedly among patients, which suggests that all EPCR-binding CIDRα1 subtypes are required to be targeted to deplete P. falciparum sequestration in host blood circulation, in particular for sequestration in brain blood circulation [11]. Several lines of evidence support a correlation between the plasma EPCR (soluble EPCR, sEPCR) levels and the genetic polymorphisms of the EPCR gene, particularly the EPCR rs867186-A/G genotype [1,2,[24][25][26]. sEPCR can competitively bind to the CIDRα1 domain and therefore displaces EPCR binding sites for APC, which restores cellular EPCR function.…”