Functional analysis of two haplotypes of the human endothelial protein C receptor gene

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 34, Issue 3, 2014, Pages 684-690

  Medina, P ^a   Navarro, S ^a   Bonet, E ^a   Martos, L ^a   Estelles A ^a   Bertina, R M ^b   Vos, H L ^b   Espana F ^a  

^a HOSPITAL UNIVERSITARIO LA FE   (Spain)

^b LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Gene expression; Human umbilical vein endothelial cells; Receptors, cell surface; Venous thromboembolism

Indexed keywords

GENE EXPRESSION; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; RECEPTORS, CELL SURFACE; VENOUS THROMBOEMBOLISM;

ACTIVATED PROTEIN C RESISTANCE; ADULT; ANTIGENS, CD; CULTURE MEDIA, CONDITIONED; ENZYME ACTIVATION; FACTOR V; FEMALE; GENETIC PREDISPOSITION TO DISEASE; GENOTYPE; HAPLOTYPES; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; INTRONS; MALE; MEMBRANE PROTEINS; MIDDLE AGED; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEIN C; PROTEIN ISOFORMS; PROTHROMBIN; PULMONARY EMBOLISM; RECEPTORS, CELL SURFACE; RISK; RNA, MESSENGER; SPAIN; THROMBOPHILIA; VENOUS THROMBOEMBOLISM;

EID: 84894588194     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.113.302518     Document Type: Article

References (29)

1. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT. The endothelial cell protein C receptor augments protein C activation by the thrombin-Thrombomodulin complex. Proc Natl Acad Sci U S A. 1996;93:10212-10216
2. Esmon CT. Protein C anticoagulant system-Anti-inflammatory effects. Semin Immunopathol. 2012;34:127-132
3. Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotective pathways. Int J Hematol. 2012;95:333-345
4. Simmonds RE, Lane DA. Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: Comparison with the structure of CD1/major histocompatibility complex alpha1 and alpha2 domains. Blood. 1999;94:632-641
5. Gu JM, Crawley JT, Ferrell G, Zhang F, Li W, Esmon NL, Esmon CT. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J Biol Chem. 2002;277:43335-43343
6. Kurosawa S, Stearns-Kurosawa DJ, Hidari N, Esmon CT. Identification of functional endothelial protein C receptor in human plasma. J Clin Invest. 1997;100:411-418
7. Qu D, Wang Y, Esmon NL, Esmon CT. Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-Alpha converting enzyme/ADAM17. J Thromb Haemost. 2007;5:395-402
8. Medina P, Navarro S, Estellés A, Vayá A, Woodhams B, Mira Y, Villa P, Migaud-Fressart M, Ferrando F, Aznar J, Bertina RM, España F. Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk. Thromb Haemost. 2004;91:905-911
9. Saposnik B, Reny JL, Gaussem P, Emmerich J, Aiach M, Gandrille S. A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood. 2004;103:1311-1318
10. Uitte de Willige S, van Marion V, Rosendaal FR, Vos HL, de Visser MC, Bertina RM. Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost. 2004;2:1305-1310
11. Medina P, Navarro S, Estellés A, España F. Polymorphisms in the endothelial protein C receptor gene and thrombophilia. Thromb Haemost. 2007;98:564-569
12. Navarro S, Medina P, Mira Y, Estellés A, Villa P, Ferrando F, Vayá A, Bertina RM, España F. Haplotypes of the EPCR gene, prothrombin levels, and the risk of venous thrombosis in carriers of the prothrombin G20210A mutation. Haematologica. 2008;93:885-891
13. Navarro S, Bonet E, Estellés A, Montes R, Hermida J, Martos L, España F, Medina P. The endothelial cell protein C receptor: Its role in thrombosis. Thromb Res. 2011;128:410-416
14. Medina P, Navarro S, Estellés A, Vayá A, Bertina RM, España F. Influence of the 4600A/G and 4678G/C polymorphisms in the endothelial protein C receptor (EPCR) gene on the risk of venous thromboembolism in carriers of the factor V Leiden mutation. Thromb Haemost. 2005;94:389-395
15. Pecheniuk NM, Elias DJ, Xu X, Griffin JH. Failure to validate association of gene polymorphisms in EPCR, PAR-1, FSAP and protein S Tokushima with venous thromboembolism among Californians of European ancestry. Thromb Haemost. 2008;99:453-455
16. Espana F, Zuazu I, Vicente V, Estellés A, Marco P, Aznar J. Quantification of circulating activated protein C in human plasma by immunoassays-enzyme levels are proportional to total protein C levels. Thromb Haemost. 1996;75:56-61
17. España F, Vayá A, Mira Y, Medina P, Estellés A, Villa P, Falcó C, Aznar J. Low level of circulating activated protein C is a risk factor for venous thromboembolism. Thromb Haemost. 2001;86:1368-1373
18. Yamagishi K, Cushman M, Heckbert SR, Tsai MY, Folsom AR. Lack of association of soluble endothelial protein C receptor and PROCR 6936A/G polymorphism with the risk of venous thromboembolism in a prospective study. Br J Haematol. 2009;145:221-226
19. Dennis J, Johnson CY, Adediran AS, de Andrade M, Heit JA, Morange PE, Trégouët DA, Gagnon F. The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: A HuGE review and meta-Analysis of evidence from observational studies. Blood. 2012;119:2392-2400
20. Reiner AP, Carty CL, Jenny NS, Nievergelt C, Cushman M, Stearns-Kurosawa DJ, Kurosawa S, Kuller LH, Lange LA. PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: The Cardiovascular Health Study. J Thromb Haemost. 2008;6:1625-1632
21. Medina P, Navarro S, Corral J, Zorio E, Roldán V, Estellés A, Santamaría A, Marín F, Rueda J, Bertina RM, España F; RECAVA Thrombosis Groups. Endothelial protein C receptor polymorphisms and risk of myocardial infarction. Haematologica. 2008;93:1358-1363
22. Ireland H, Konstantoulas CJ, Cooper JA, et al. EPCR Ser219Gly: Elevated sEPCR, F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro. Atherosclerosis. 2005;183:283-292
23. Butterworth AS, Braund PS, Farrall M, et al; IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet. 2011;7:e1002260
24. Qu D, Wang Y, Song Y, Esmon NL, Esmon CT. The Ser219->Gly dimorphism of the endothelial protein C receptor contributes to the higher soluble protein levels observed in individuals with the A3 haplotype. J Thromb Haemost. 2006;4:229-235
25. Saposnik B, Lesteven E, Lokajczyk A, Esmon CT, Aiach M, Gandrille S. Alternative mRNA is favored by the A3 haplotype of the EPCR gene PROCR and generates a novel soluble form of EPCR in plasma. Blood. 2008;111:3442-3451
26. Tang W, Basu S, Kong X, Pankow JS, Aleksic N, Tan A, Cushman M, Boerwinkle E, Folsom AR. Genome-wide association study identifies novel loci for plasma levels of protein C: The ARIC study. Blood. 2010;116:5032-5036
27. Molina E, Hermida J, López-Sagaseta J, Puy C, Montes R. The functional properties of a truncated form of endothelial cell protein C receptor generated by alternative splicing. Haematologica. 2008;93:878-884
28. Navarro S, Medina P, Bonet E, et al. Association of the thrombomodulin gene c.1418C>T polymorphism with thrombomodulin levels and with venous thrombosis risk. Arterioscler Thromb Vasc Biol. 2013;33:1435-1440
29. Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: An online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67