title: Haplotypes of the endothelial protein C receptor (EPCR) gene are not associated with severe malaria in Tanzania.
abstract: BACKGROUND
  Endothelial 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.
  
  
  METHODS
  Study 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.
  
  
  RESULTS
  Individuals 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.
  
  
  CONCLUSIONS
  Frequencies 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.
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. Hellehan@sund.ku.dk.|Department of Clinical Microbiology and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen Ø, Denmark. Hellehan@sund.ku.dk.
authors.forename: Helle Holm
authors.initials: HH
authors.lastname: Hansson
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. lturner@sund.ku.dk.|Department of Clinical Microbiology and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen Ø, Denmark. lturner@sund.ku.dk.
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. linemoeller89@gmail.com.|Department of Clinical Microbiology and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen Ø, Denmark. linemoeller89@gmail.com.
authors.forename: Line
authors.initials: L
authors.lastname: Møller
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. cwang@sund.ku.dk.|Department of Clinical Microbiology and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen Ø, Denmark. cwang@sund.ku.dk.
authors.forename: Christian William
authors.initials: CW
authors.lastname: Wang
authors.affiliation: Tanga Research Centre, National Institute for Medical Research, Bombo Area, PO Box 5004, Tanga, United Republic of Tanzania. minjartd@yahoo.com.
authors.forename: Daniel T R
authors.initials: DT
authors.lastname: Minja
authors.affiliation: Tanga Research Centre, National Institute for Medical Research, Bombo Area, PO Box 5004, Tanga, United Republic of Tanzania. Sgesase@yahoo.com.
authors.forename: Samwel
authors.initials: S
authors.lastname: Gesase
authors.affiliation: Tanga Research Centre, National Institute for Medical Research, Bombo Area, PO Box 5004, Tanga, United Republic of Tanzania. b.mmbando@yahoo.com.
authors.forename: Bruno
authors.initials: B
authors.lastname: Mmbando
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. iby@sund.ku.dk.|Department of Clinical Microbiology and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen Ø, Denmark. iby@sund.ku.dk.
authors.forename: Ib Christian
authors.initials: IC
authors.lastname: Bygbjerg
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. thor@sund.ku.dk.|Department of Clinical Microbiology and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen Ø, Denmark. thor@sund.ku.dk.
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. jpalusingu@gmail.com.|Tanga Research Centre, National Institute for Medical Research, Bombo Area, PO Box 5004, Tanga, United Republic of Tanzania. jpalusingu@gmail.com.
authors.forename: John P A
authors.initials: JP
authors.lastname: Lusingu
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. micali@sund.ku.dk.|Department of Clinical Microbiology and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen Ø, Denmark. micali@sund.ku.dk.
authors.forename: Michael
authors.initials: M
authors.lastname: Alifrangis
authors.affiliation: Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Science, University of Copenhagen, Østerfarimagsgade 5, Building 22-23, 1356, Copenhagen K, Denmark. thomasl@sund.ku.dk.|Department of Clinical Microbiology and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Blegdamsvej 9, 2100, Copenhagen Ø, Denmark. thomasl@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
mesh_terms: D000293:Adolescent; D015703:Antigens, CD / Q000097:blood* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D060467:Disease Resistance; D000074283:Endothelial Protein C Receptor; D005260:Female; D006239:Haplotypes; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000097:blood* / Q000235:genetics*; D013636:Tanzania
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011956:Receptors, Cell Surface