Download PDF
Thromb Haemost 2005; 94(02): 389-394
DOI: 10.1160/TH05-02-0089
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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 factor V Leiden

Pilar Medina
1   Research Center, Valencia, Spain
,
Silvia Navarro
1   Research Center, Valencia, Spain
,
Amparo Estellés
1   Research Center, Valencia, Spain
,
Amparo Vayá
2   Department of Clinical Pathology, La Fe University Hospital, Valencia, Spain
,
Rogier M. Bertina
3   Hemostasis and Thrombosis Research Centre, Department of Hematology, Leiden University Medical Centre, Leiden, The Netherlands
,
Francisco España
1   Research Center, Valencia, Spain
› Author AffiliationsFinancial support: This work was partially supported by research grants from Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, PI020125 and PI020136), from Fundación Mutua Madrileña, and from Generalitat Valenciana-Consellería de Empresa, Universidad y Ciencia (Grupos03/ 010), Spain. S. Navarro was the recipient of a fellowship from Fundación Española de Trombosis y Hemostasia (FETH), Spain
Further Information

Publication History

Received: 04 February 2005

Accepted after major revision: 19 May 2005

Publication Date:
05 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Two polymorphisms in the endothelial protein C receptor (EPCR) gene, 4600A/G and 4678G/C, have been reported to influence the risk of venous thromboembolism (VTE). The objective of this study was to assess whether these polymorphisms modify the risk of VTE in carriers of factor V (FV) Leiden. We genotyped 295 carriers of FV Leiden for these polymorphisms: 100 unrelated patients with a history ofVTE (propositi) and 195 relatives (14 of them symptomatic) of 81 of the propositi. Spontaneous VTE events occurred in 71% of propositi carrying the 4678GG genotype, 65% carrying the GC, and 43% with the CC genotype. The mean age at the first onset was significantly higher in propositi carrying the 4678CC than in those with the GC or GG genotype (p=0.046). Among the 276 carriers of FV Leiden from the 81 families studied, the 95 symptomatic members had similar 4600G allele and 4600AG genotype frequencies but significantly lower 4678C allele (p=0.002) and 4678CC genotype (p=0.004) frequencies than the 181 asymptomatic members. The probability of being free of thrombosis at age 40 was significantly higher in the 66 carriers of the 4678CC genotype (94%) than in the 138 carrying the GC (72%) or in the 72 with the 4678GG genotype (60%) (p<0.001). Multivariate analysis showed that the 4678CC genotype reduced the risk of thrombosis in carriers of FV Leiden (OR=0.31;95% CI=0.16–0.83). The incidence ofVTE was higher in the 195 relatives with FV Leiden than in the 133 without FV Leiden (OR=4.7; CI=1.3–7.2). These results show that carriers of FV Leiden with the 4678CC genotype have a significantly reduced risk of VTE compared with those carrying the 4678GG or GC genotype, probably due to the higherAPC levels previously observed in individuals carrying the 4678CC genotype.

Keywords

Endothelial protein C receptor - factor V Leiden - venous thromboembolism - polymorphisms - survival time - interaction
 

  • References

  • 1 Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb 1992; 12: 135-45.
    CrossrefPubMedSearch in Google Scholar
  • 2 Stearns-Kurosawa DJ, Kurosawa S, Mollica JS. et al. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 1996; 93: 10212-6.
    CrossrefPubMedSearch in Google Scholar
  • 3 Dahlbäck B. Inherited resistance to activated protein C, a major basis of venous thrombosis, is caused by deficient anticoagulant cofactor function of factor V. Haematologica 1995; 80 (Suppl. 02) 102-13.
    PubMedSearch in Google Scholar
  • 4 Bertina R, Koeleman B, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
    CrossrefPubMedSearch in Google Scholar
  • 5 De Stefano V, Rossi E, Paciaroni K. et al. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica 2002; 7: 1095-108.
    PubMedSearch in Google Scholar
  • 6 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-62.
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-21.
    CrossrefPubMedSearch in Google Scholar
  • 8 Seligshon U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78: 297-301.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Vandenbroucke JP, Koster T, Briët E. et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.
    CrossrefPubMedSearch in Google Scholar
  • 10 Makris M, Preston FE, Beauchamp NJ. et al. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Koeleman BP, Reitsma PH, Allaart CF. et al. Activated protein C resistance as an additional risk factor of thrombosis in protein C-deficient families. Blood 1994; 84: 1031-5.
    CrossrefPubMedSearch in Google Scholar
  • 12 Zöller B, Berntsdotter A, García de Frutos P. et al Resistance to activated protein C as an additional gen- etic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-23.
    CrossrefPubMedSearch in Google Scholar
  • 13 España F, Medina P, Mira Y. et al. A new polymorphism in the 3’UTR of the endothelial protein C receptor is associated with increased levels of circulating activated protein C and decreased risk of venous thrombosis. J Thromb Haemost. (Suppl) July 2001 Abstract OC885.
    PubMedSearch in Google Scholar
  • 14 Saposnik B, Reny JL, Gausem P. et al. 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: 1311-8.
    CrossrefPubMedSearch in Google Scholar
  • 15 Medina P, Navarro S, Estellés A. et al. 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: 905-11.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Uitte de Willige S, van Marion V, Rosendaal FR. et al. Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost 2004; 2: 1305-10.
    CrossrefPubMedSearch in Google Scholar
  • 17 Gandrille S, Alhenc-Gelas M, Aiach M. A rapid screening method for the factor V Arg 506 Gln mutation. Blood Coagul Fibrinolysis 1995; 6: 245-7.
    CrossrefPubMedSearch in Google Scholar
  • 18 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variant in the 3´-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and increase in venous thrombosis. Blood 1996; 88: 3698-703.
    CrossrefPubMedSearch in Google Scholar
  • 19 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 α1 and α2 domains. Blood 1999; 94: 632-41.
    CrossrefPubMedSearch in Google Scholar
  • 20 Lensen RPM, Bertina RM, de Ronde H. et al. Venous thrombotic risk in family members of unselected individuals with factor V Leiden. Thromb Haemost 2000; 83: 817-21.
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Middeldorp S, Henkens CMA, Koopman MMW. et al. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med 1998; 128: 15-20.
    CrossrefPubMedSearch in Google Scholar
  • 22 Simioni P, Sanson BJ, Prandoni P. et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81: 198-202.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 España F, Vayá A, Mira Y. et al. Low level of circulating activated protein C is a risk factor for venous thrombosis. Thromb Haemost 2001; 86: 1368-73.
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Petäjä J, Hakala L, Rasi V. et al. Circulating activated protein C in subjects with heterozygous Gln506-factorV. Haemostasis 1998; 28: 31-6.
    PubMedSearch in Google Scholar
  • 25 Xu J, Esmon NL, Esmon CT. Reconstitution of the human endothelial cell protein C receptor with thrombomodulin in phosphatidylcholine vesicles enhances protein C activation. J Biol Chem 1999; 274: 6704-10.
    CrossrefPubMedSearch in Google Scholar
  • 26 Tazawa R, Yamamoto K, Suzuki K. et al. Presence of functional cyclic AMP responsive element in the 3’-untranslated region of the human thrombomodulin gene. Biochem Biophys Res Commun 1994; 200: 1391-7.
    CrossrefPubMedSearch in Google Scholar
  • 27 Tebo JM, Datta S, Kisbore R. et al. Interleukin-1 mediated stabilization of mouse KC mRNA depends on sequences in both 5’- and 3’-untranslated regions. J Biol Chem 2000; 275: 12987-93.
    CrossrefPubMedSearch in Google Scholar
  • 28 Zoller B, García de Frutos P, Hillarp A. et al. Thrombophilia as a multigenic disease. Haematologica 1999; 84: 59-70.
    PubMedSearch in Google Scholar
  • 29 Aznar J, Vayá A, Estellés A. et al. Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000; 85: 1271-6.
    PubMedSearch in Google Scholar
  • 30 Tirado I, Mateo J, Soria JM. et al. Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies. Haematologica 2001; 86: 1200-8.
    PubMedSearch in Google Scholar
  • 31 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-73.
    CrossrefPubMedSearch in Google Scholar