Association of the endothelial protein C receptor (PROCR) rs867186-G allele with protection from severe malaria.

Cytoadhesion of Plasmodium falciparum-infected erythrocytes to endothelial cells in microvessels is a remarkable characteristic of severe malaria. The endothelial protein C receptor (EPCR), encoded by the endothelial protein C receptor gene (PROCR), has recently been identified as an endothelial receptor for specific P. falciparum erythrocyte membrane protein 1 (PfEMP1) subtypes containing domain cassettes (DCs) 8 and 13. The PROCR rs867186-G allele (serine-to-glycine substitution at position 219 of EPCR; 219Gly) has been shown to be associated with higher levels of plasma soluble EPCR (sEPCR). In this study, the association of PROCR rs867186 with severe malaria is examined in Thai population. A total of 707 Thai patients with P. falciparum malaria (341 with severe malaria and 336 with mild malaria) were genotyped for rs867186. To assess the association of PROCR rs867186 with severe malaria, three models (dominant, recessive and allelic) were evaluated. The rates of non-synonymous and synonymous substitutions were estimated for the coding sequence of the PROCR gene. The rs867186-GG genotype was significantly associated with protection from severe malaria (P-value=0.026; odds ratio=0.33; 95% confidence interval=0.12-0.90). Evolutionary analysis provided no evidence of strong positive selection acting on the PROCR gene. The rs867186-GG genotype showed significant association with protection from severe malaria. The present results suggest that PfEMP1-EPCR interaction, which can mediate cytoadhesion and/or reduce cytoprotective and anti-inflammatory effects, is crucial to the pathogenesis of severe malaria.