High levels of protein C are determined by PROCRhaplotype 3

Background:Genetic determinants of plasma levels of protein C (PC) are poorly understood. Recently, we identified a locus on chromosome 20 determining high PC levels in a large Dutch pedigree with unexplained thrombophilia. Candidate genes in the LOD‐1 support interval included FOXA2, THBDand PROCR. Objectives:To examine these candidate genes and their influence on plasma levels of PC. Patients/Methods:Exons, promoter and 3′UTR of the candidate genes were sequenced in 12 family members with normal to high PC levels. Four haplotypes of PROCR, two SNPs in the neighboring gene EDEM2and critical SNPs encountered during resequencing were genotyped in the family and in a large group of healthy individuals (the Leiden Thrombophilia Study (LETS) controls). Soluble endothelial protein C receptor (sEPCR) and soluble thrombomodulin (sTM) plasma levels were measured in the family. Results:PROCRhaplotype 3 (H3) and FOXA2rs1055080 were associated with PC levels in the family but only PROCRH3 was also associated with plasma levels in the healthy individuals. Carriers of both variants had higher PC levels than carriers of only PROCR H3in the family but not in healthy individuals, suggesting that a second determinant is present. EDEM2SNPs were associated with PC levels, but their effect was small. PC and sEPCR levels were associated in both studies. sTM was not associated with variations of THBDor PC levels. Conclusions:Chromosome 20 harbors genetic determinants of PC and sEPCR levels and the analysis of candidate genes suggests that the PROCRlocus is responsible.