The A6936G polymorphism of the endothelial protein C receptor gene is associated with the risk of unexplained foetal loss in Mediterranean European couples

 

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Summary

The endothelial protein C receptor (EPCR) is expressed by trophoblast cells. Mid-gestation pregnancy loss is described in animals with a haemochorial placenta lacking EPCR. The A6936G allele of the EPCR gene (PROCR) may be associated with lower EPCR densities on trophoblasts, but data are lacking for its effect on the risk of pregnancy loss in humans. A 1:2 case-control study on unexplained pregnancy loss was nested in the NOHA First cohort: 3,218 case couples and 6,436 control couples were studied for PROCR A6936G, coagulation factor V gene (F5) G1691A and coagulation factor II gene (F2) G20210A polymorphisms. Ethnicity and time of pregnancy loss defined through biometry-based gestational ages (embryonic loss < 10^th week ≥ foetal loss) were analysed. The PROCR A6936G allele, in mothers and fathers, was associated only with foetal loss in both Europeans and non-Europeans. Increasing probability levels of carrying a homozygous child were increasingly associated with the risk of foetal demise. The F5 G1691A and F2 G20210A alleles, only in mothers, were only and independently associated with foetal loss in Europeans. In our population, the PROCR A6936G allele describes women, but also men and thus couples, at risk for first unexplained foetal loss. This risk is independent of the foetal loss risk conferred to our local Mediterranean European women by the F5 G1691A and F2 G20210A alleles. Data confirm that the relationship between thrombophilias and pregnancy loss varies according to ethnicity and loss type.

^* * These four co-authors contributed equally to the work.

• References

• 1 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-908.
  CrossrefPubMedGoogle Scholar
• 2 Kovalevsky G, Gracia CR, Berlin JA. et al. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss. Arch Intern Med 2004; 164: 558-563.
  CrossrefPubMedGoogle Scholar
• 3 Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost 2004; 91: 700-711.
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Robertson L, Wu O, Langhorne P. et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171-196.
  CrossrefPubMedGoogle Scholar
• 5 Kist WJ, Janssen NG, Kalk JJ. et al. Thrombophilias and adverse pregnancy outcome - A confounded problem!. Thromb Haemost 2008; 99: 77-85.
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Gu JM, Crawley JT, Ferrel G. et al. 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.
  CrossrefPubMedGoogle Scholar
• 7 Crawley JTB, Gu JM, Ferrell G. et al. Distribution of endothelial cell protein / activated protein C receptor EPCR) during mouse embryo development. Thromb Haemost 2002; 88: 259-266.
  Article in Thieme ConnectPubMedGoogle Scholar
• 8 Isermann B, Sood R, Pawlinski R. et al. The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med 2003; 09: 331-337.
  CrossrefPubMedGoogle Scholar
• 9 Li W, Zheng X, Gu JM. et al. Extraembryonic expression of EPCR is essential for embryonic viability. Blood 2005; 106: 2716-2722.
  CrossrefPubMedGoogle Scholar
• 10 Sood R, Kalloway S, Mast AE. et al. Fetomaternal cross talk in the placental vascular bed: control of coagulation by trophoblast cells. Blood 2006; 107: 3173-3180.
  CrossrefPubMedGoogle Scholar
• 11 Kurosawa S, Stearns-Kurosawa DJ, Hidari N. et al. Identification of functional endothelial protein C receptor in human plasma. J Clin Invest 1997; 100: 411-418.
  CrossrefPubMedGoogle Scholar
• 12 Qu D, Wang Y, Esmon NL. et al. Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-? converting enzyme/ADAM17. J Thromb Haemost 2007; 05: 395-402.
  CrossrefPubMedGoogle Scholar
• 13 Saposnik B, Lesteven E, Lokajczyk A. et al. 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.
  CrossrefPubMedGoogle Scholar
• 14 Saposnik B, Reny JL, Guaussem 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 2003; 103: 1311-1318.
  CrossrefPubMedGoogle Scholar
• 15 Navarro S, Medina P, Mira Y. et al. Haplotypes of the EPCR gene, prothrombin levels and the risk of venous trombosis in carriers of the prothrombin G20210A mutation. Haematologica 2008; 93: 885-891.
  CrossrefPubMedGoogle Scholar
• 16 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: 905-911.
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Uitte de Willige S, van Marion V, Rosendaal FR. et al. Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep vein thrombosis. J Thromb Haemost 2004; 02: 1305-1310.
  CrossrefPubMedGoogle Scholar
• 18 Qu D, Wang Y, Song Y. et al. The Ser219>Gly dimorphism in the endothelial protein C receptor contributes to the higher soluble protein levels observed in individuals with the A3 haplotype. J Thromb Haemost 2006; 04: 229-35.
  PubMedGoogle Scholar
• 19 Hurtado V, Montes R, Gris JC. et al. Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for fetal death. Blood 2004; 104: 1369-1374.
  CrossrefPubMedGoogle Scholar
• 20 Lavigne-Lissalde G, Cochery-Nouvellon E, Mercier E. et al. High plasma levels of endothelial protein C receptor are associated with the risk of unexplained foetal death. J Thromb Haemost 2005; 03: 393-395.
  CrossrefPubMedGoogle Scholar
• 21 Lissalde-Lavigne G, Fabbro-Peray P, Cochery-Nouvelon E. et al. Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control “NOHA First” study. J Thromb Haemost 2005; 03: 2178-2184.
  CrossrefPubMedGoogle Scholar
• 22 Cochery-Nouvellon E, Mercier E, Lissalde-Lavigne G. et al. Homozygosity for the C46T polymor- phism of the F12 gene is a risk factor for venous thrombosis during the first pregnancy. J Thromb Haemost 2007; 05: 700-707.
  CrossrefPubMedGoogle Scholar
• 23 Wisser J, Dirschedl P, Krone S. Estimation of gestational age by transvaginal sonographic measurement of greatest embryonic length in dated human embryos. Ultrasound Obstet Gynecol 1994; 04: 457-462.
  CrossrefPubMedGoogle Scholar
• 24 Salomon LJ, Duyme M, Crequat J. et al. French fetal biometry: reference equations and comparison with other charts. Ultrasound Obstet Gynecol 2006; 28: 193-198.
  CrossrefPubMedGoogle Scholar
• 25 Ireland H, Konstantoulas CJ, Cooper AJ. et al. EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk of coronary heart disease, and increased sEPCR shedding in vitro. Atherosclerosis 2005; 183: 283-292.
  CrossrefPubMedGoogle Scholar
• 26 Kaare M, Ulander VM, Painter JN. et al. Variations in the thrombomodulin and endothelial protein C receptor genes in couples with recurrent miscarriages. Hum Reprod 2007; 22: 864-868.
  CrossrefPubMedGoogle Scholar
• 27 Hopmeier P, Puehringer H, van Trotsenburg M. et al. Association of endothelial protein C receptor haplotypes, factor V Leiden and recurrent first trimester pregnancy loss. Clin Biochem 2008; 41: 1022-1024.
  CrossrefPubMedGoogle Scholar
• 28 Girardi G, Redecah P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10: 1222-1226.
  CrossrefPubMedGoogle Scholar
• 29 Lay AJ, Linag Z, Rosen ED. et al. Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capacities. J Clin Invest 2005; 115: 1552-1561.
  CrossrefPubMedGoogle Scholar
• 30 Sood R, Zogg M, Westrick RJ. et al. Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers. J Exp Med 2007; 204: 1049-1056.
  CrossrefPubMedGoogle Scholar
• 31 Pasquier E, Bohec C, Mottier D. et al. inherited thrombophilias and unexplained pregnancy loss: an incident case-control study. J Thromb Haemost 2009; 07: 306-311.
  CrossrefPubMedGoogle Scholar