Haplotypes of the endothelial protein C receptor (EPCR) gene are not associated with severe malaria in Tanzania

Abstract

BackgroundEndothelial protein C receptor (EPCR) was recently identified as a key receptor for Plasmodium falciparum erythrocyte membrane protein 1 mediating sequestration of P. falciparum-infected erythrocytes in patients suffering from severe malaria. Soluble EPCR (sEPCR) inhibits binding of P. falciparum to EPCR in vitro and increased levels of sEPCR have been associated with the H3 haplotype of the EPCR encoding PROCR gene. It has been hypothesized that elevated sEPCR levels, possibly linked to the PROCR H3 genetic variant, may confer protection against severe forms of malaria. This study determined the frequencies of PROCR haplotypes H1–4 and plasma levels of sEPCR in a Tanzanian study population to investigate a possible association with severe malaria. MethodsStudy participants were children under 5 years of age admitted at the Korogwe District Hospital (N = 143), and diagnosed as having severe malaria (N = 52; including cerebral malaria N = 17), uncomplicated malaria (N = 24), or an infection other than malaria (N = 67). In addition, blood samples from 71 children living in nearby villages were included. The SNPs defining the haplotypes of PROCR gene were determined by post-PCR ligation detection reaction-fluorescent microsphere assay.ResultsIndividuals carrying at least one H3 allele had significantly higher levels of sEPCR than individuals with no H3 alleles (P < 0.001). No difference in the frequency of H3 was found between the non-malaria patients, malaria patients or the village population (P > 0.1). Plasma levels of sEPCR differed between these three groups, with higher sEPCR levels in the village population compared to the hospitalized patients (P < 0.001) and higher levels in malaria patients compared to non-malaria patients (P = 0.001). However, no differences were found in the distribution of H3 (P = 0.2) or levels of sEPCR (P = 0.8) between patients diagnosed with severe and uncomplicated malaria.ConclusionFrequencies of SNPs determining PROCR haplotypes were in concordance with other African studies. The PROCR H3 allele was associated with higher levels of sEPCR, confirming earlier findings, however, in this Tanzanian population; neither PROCR haplotype nor level of sEPCR was associated with severe malaria, however, larger studies are needed to confirm these findings.

Plasma Ang2 and ADAM17 levels are elevated during clinical malaria; Ang2 level correlates with severity and expression of EPCR-binding PfEMP1

“…None were malaria positive at follow-up by rapid diagnostic tests. 32 of the children admitted to Korogwe District Hospital with infectious diseases other than malaria were included as non-malaria hospitalized children and also a part of a previous study34 (Supplementary Table S1). The patient samples included in this study were selected from a database to reflect the main clinical manifestations associated with high mortality; (I) CM was diagnosed if the Blantyre coma score was <335), (II) SMA if the haemoglobin (Hb) level was <5 g/dl, (III) if there were clinical signs of RD (Kussmaul deep breathing and/or chest indrawing), or (IV) if hyperparasitaemia was observed (>200,000 parasites/μl).…”

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.…”

“…Severe malaria (SM) is defined as cerebral malaria (CM), severe malaria anemia (SMA), or malaria patients with high levels of parasitemia, hypoglycemia, and increased creatinine, which demonstrates high mortality in patients with P. falciparum infections [1,2]. The pathological feature of SM is the sequestration of pRBC to host microvasculature beds in a variety of organs and tissues due to their binding to endothelial cells (known as cytoadherence) via the P. falciparum erythrocyte membrane protein 1 (PfEMP1) [3][4][5][6][7][8][9].…”

“…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.…”

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

“…which is indicative of high mortality among patients with P. falciparum infections [1,2]. The pathological feature of SM is the sequestration of pRBC to host microvasculature beds in a variety of organs and tissues.…”