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Sci Rep. 2016 Jun 3;6:27084. doi: 10.1038/srep27084.

The endothelial protein C receptor rs867186-GG genotype is associated with increased soluble EPCR and could mediate protection against severe malaria.

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Department of Pediatrics, Division of Global Pediatrics, University of Minnesota, 2001 6th Street SE, Minneapolis, MN, 55455, USA.
Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN, 46202, USA.
Department of Pediatrics and Child Health, Makerere University School of Medicine, PO Box 7072, Kampala, Uganda.
Department of Psychiatry, Makerere University School of Medicine, PO Box 7072, Kampala, Uganda.
Department of Medicine, University of Minnesota Medical School, 401 East River Parkway, Minneapolis, MN, 55455, USA.
Division of Biostatistics, University of Minnesota School of Public Health, 420 Delaware St SE, Minneapolis, MN, 55455, USA.
Centre for Medical Parasitology, Department of International Health, Immunology &Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Tagensvej 20, 2200, Copenhagen, Denmark.


The endothelial protein C receptor (EPCR) appears to play an important role in Plasmodium falciparum endothelial cell binding in severe malaria (SM). Despite consistent findings of elevated soluble EPCR (sEPCR) in other infectious diseases, field studies to date have provided conflicting data about the role of EPCR in SM. To better define this role, we performed genotyping for the rs867186-G variant, associated with increased sEPCR levels, and measured sEPCR levels in two prospective studies of Ugandan children designed to understand immunologic and genetic factors associated with neurocognitive deficits in SM including 551 SM children, 71 uncomplicated malaria (UM) and 172 healthy community children (CC). The rs867186-GG genotype was more frequent in CC (4.1%) than SM (0.6%, P = 0.002). The rs867186-G variant was associated with increased sEPCR levels and sEPCR was lower in children with SM than CC (P < 0.001). Among SM children, those who had a second SM episode showed a trend toward lower plasma sEPCR both at initial admission and at 6-month follow-up compared to those without repeated SM (P = 0.06 for both). The study findings support a role for sEPCR in severe malaria pathogenesis and emphasize a distinct role of sEPCR in malaria as compared to other infectious diseases.

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