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, THBD and 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 EDEM2 and 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: PROCR haplotype 3 (H3) and FOXA2 rs1055080 were associated with PC levels in the family but only PROCR H3 was also associated with plasma levels in the healthy individuals. Carriers of both variants had higher PC levels than carriers of only PROCR H3 in the family but not in healthy individuals, suggesting that a second determinant is present. EDEM2 SNPs 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 THBD or PC levels. CONCLUSIONS: Chromosome 20 harbors genetic determinants of PC and sEPCR levels and the analysis of candidate genes suggests that the PROCR locus is responsible.
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, THBD and 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 EDEM2 and 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:PROCR haplotype 3 (H3) and FOXA2rs1055080 were associated with PC levels in the family but only PROCR H3 was also associated with plasma levels in the healthy individuals. Carriers of both variants had higher PC levels than carriers of only PROCR H3 in the family but not in healthy individuals, suggesting that a second determinant is present. EDEM2 SNPs 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 THBD or PC levels. CONCLUSIONS: Chromosome 20 harbors genetic determinants of PC and sEPCR levels and the analysis of candidate genes suggests that the PROCR locus is responsible.
Authors: Georgios Athanasiadis; Alfonso Buil; Juan Carlos Souto; Montserrat Borrell; Sonia López; Angel Martinez-Perez; Mark Lathrop; Jordi Fontcuberta; Laura Almasy; José Manuel Soria Journal: PLoS One Date: 2011-12-28 Impact factor: 3.240
Authors: David Stacey; Lingyan Chen; Paulina J Stanczyk; Joanna M M Howson; Amy M Mason; Stephen Burgess; Stephen MacDonald; Jonathan Langdown; Harriett McKinney; Kate Downes; Neda Farahi; James E Peters; Saonli Basu; James S Pankow; Weihong Tang; Nathan Pankratz; Maria Sabater-Lleal; Paul S de Vries; Nicholas L Smith; Amy D Gelinas; Daniel J Schneider; Nebojsa Janjic; Nilesh J Samani; Shu Ye; Charlotte Summers; Edwin R Chilvers; John Danesh; Dirk S Paul Journal: Nat Commun Date: 2022-03-09 Impact factor: 17.694
Authors: Louise Turner; Thomas Lavstsen; Sanne S Berger; Christian W Wang; Jens E V Petersen; Marion Avril; Andrew J Brazier; Jim Freeth; Jakob S Jespersen; Morten A Nielsen; Pamela Magistrado; John Lusingu; Joseph D Smith; Matthew K Higgins; Thor G Theander Journal: Nature Date: 2013-06-05 Impact factor: 49.962