期刊论文详细信息
BMC Medical Genetics
Association of soluble endothelial protein C receptor plasma levels and PROCR rs867186 with cardiovascular risk factors and cardiovascular events in coronary artery disease patients: The Athero Gene Study
Pierre-Emmanuel Morange3  David-Alexandre Tregouet5  Thomas Munzel1  Christoph Bickel2  Hans J Rupprecht1  Renate Schnabel4  Stefan Blankenberg4  Noémie Saut3  William Cohen3  Choumous Kallel3 
[1] Department of Medicine II, Johannes Gutenberg-University Mainz, Mainz, Germany;Federal Armed Forces Central Hospital Koblenz, Koblenz, Germany;INSERM UMR_1062, Aix-Marseille Université, Marseille, F-13385, France;Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany;INSERM, UMR_S 937; Institute of Cardiometabolism And Nutrition (ICAN), Université Pierre et Marie Curie Paris 6, Paris, F-75013, France
关键词: Coronary artery disease;    Endothelial protein C receptor;    Protein C;    Haemostasis;    \;   
Others  :  1177778
DOI  :  10.1186/1471-2350-13-103
 received in 2012-07-31, accepted in 2012-10-12,  发布年份 2012
PDF
【 摘 要 】

Background

Blood coagulation is an essential determinant of coronary artery disease (CAD). Soluble Endothelial Protein C Receptor (sEPCR) may be a biomarker of a hypercoagulable state. We prospectively investigated the relationship between plasma sEPCR levels and the risk of cardiovascular events (CVE).

Methods

We measured baseline sEPCR levels in 1673 individuals with CAD (521 with acute coronary syndrome [ACS] and 1152 with stable angina pectoris [SAP]) from the AtheroGene cohort. During a median follow up of 3.7 years, 136 individuals had a CVE. In addition, 891 of these CAD patients were genotyped for the PROCR rs867186 (Ser219Gly) variant.

Results

At baseline, sEPCR levels were similar in individuals with ACS and SAP (median: 111 vs. 115 ng/mL respectively; p=0.20). Increased sEPCR levels were found to be associated with several cardiovascular risk factors including gender (p=0.006), soluble Tissue Factor levels (p=0.0001), diabetes (p=0.0005), and factors reflecting impaired renal function such as creatinine and cystatin C (p<0.0001). sEPCR levels were not significantly associated with the risk of CVE (median: 110 and 114 ng/mL in individuals with and without future CVE respectively; p=0.68). The rs867186 variant was found to explain 59% of sEPCR levels variability (p<10-200) but did not associate with CVE risk.

Conclusion

Our findings show that in patients with CAD, circulating sEPCR levels are related to classical cardiovascular risk factors and renal impairment but are not related to long-term incidence of CVE.

【 授权许可】

   
2012 Kallel et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20150504023847545.pdf 203KB PDF download
【 参考文献 】
  • [1]World Health Organisation. Cardiovascular media-centre disease. www.who.int webcite
  • [2]Lowe GD: Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J Thromb Haemost 2005, 3:1618-1627.
  • [3]Castellino FJ, Ploplis VA: The protein C pathway and pathologic processes. J Thromb Haemost 2009, 7:140-145.
  • [4]Menschikowski M, Hagelgans A, Eisenhofer G, et al.: Regulation of endothelial protein C receptor shedding by cytokines is mediated through differential activation of MAP kinase signaling pathways. Exp Cell Res 2009, 315:2673-2682.
  • [5]Laszik Z, Mitro A, Taylor FB Jr, et al.: Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 1997, 96:3633-3640.
  • [6]Ye X, Fukudome K, Tsuneyoshi N, et al.: The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. Biochem Biophys Res Commun 1999, 259:671-677.
  • [7]Esmon CT: Structure and functions of the endothelial cell protein C receptor. Crit Care Med 2004, 32:S298-S301.
  • [8]Esmon CT: The endothelial cell protein C receptor. Thromb Haemost 2000, 83:639-643.
  • [9]Cheng T, Liu D, Griffin JH, et al.: Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 2003, 9:338-342.
  • [10]Xu J, Qu D, Esmon NL, et al.: Metalloproteolytic release of endothelial cell protein C receptor. J Biol Chem 2000, 275:6038-6044.
  • [11]Qu D, Wang Y, Esmon NL, et al.: Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-alpha converting enzyme/ADAM17. J Thromb Haemost 2007, 5:395-402.
  • [12]Liaw PC, Neuenschwander PF, Smirnov MD, et al.: Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. J Biol Chem 2000, 275:5447-5452.
  • [13]Kurosawa S, Esmon CT, Stearns-Kurosawa DJ: The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18. J Immunol 2000, 165:4697-4703.
  • [14]Stearns-Kurosawa DJ, Swindle K, D'Angelo A, et al.: Plasma levels of endothelial protein C receptor respond to anticoagulant treatment. Blood 2002, 99:526-530.
  • [15]Lopez-Sagaseta J, Montes R, Puy C, et al.: Binding of factor VIIa to the endothelial cell protein C receptor reduces its coagulant activity. J Thromb Haemost 2007, 5:1817-1824.
  • [16]Kurosawa S, Stearns-Kurosawa DJ, Carson CW, et al.: Plasma levels of endothelial cell protein C receptor are elevated in patients with sepsis and systemic lupus erythematosus: lack of correlation with thrombomodulin suggests involvement of different pathological processes. Blood 1998, 91:725-727.
  • [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 venous thrombosis. J Thromb Haemost 2004, 2:1305-1310.
  • [18]Medina P, Navarro S, Corral J, et al.: Endothelial protein C receptor polymorphisms and risk of myocardial infarction. Haematologica 2008, 93:1358-1363.
  • [19]Ireland HA, Cooper JA, Drenos F, et al.: FVII, FVIIa, and downstream markers of extrinsic pathway activation differ by EPCR Ser219Gly variant in healthy men. Arterioscler Thromb Vasc Biol 2009, 29:1968-1974.
  • [20]Medina P, Navarro S, Estelles 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.
  • [21]Saposnik B, Reny JL, Gaussem 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, 103:1311-1318.
  • [22]Yamagishi K, Cushman M, Heckbert SR, et al.: 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.
  • [23]Ireland H, Konstantoulas CJ, Cooper JA, et al.: EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro. Atherosclerosis 2005, 183:283-292.
  • [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 andgenerates a novel soluble form of EPCR in plasma. Blood 2008, 111:3442-5126.
  • [26]Rupprecht HJ, Blankenberg S, Bickel C, et al.: Impact of viral and bacterial infections burden on long-term prognosis in patients with coronary artery disease. Circulation 2001, 104:25-31.
  • [27]Tregouet DA, Schnabel R, Alessi MC, et al.: Activated thrombin activatable fibrinolysis inhibitor levels are associated with the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2009, 7:49-57.
  • [28]Wild PS, Zeller T, Schillert A, et al.: A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease. Circ Cardiovasc Genet 2011, 4:403-412.
  • [29]Sasieni PD: From genotypes to genes: doubling the sample size. Biometrics 1997, 53:1253-1261.
  • [30]Trégouët DA, Garelle V: A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies. Bioinformatics 2007, 23:1038-1039.
  • [31]Guitton C, Gerard N, Quillard T, et al.: Circulating endothelial cell protein C receptor: endothelial regulation and cumulative impact of gender and a3 haplotype. J Vasc Res 2011, 48:336-346.
  • [32]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 andrisk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies. Blood 2012, 119:2392-2400.
  • [33]Morange PE, Blankenberg S, Alessi MC, et al.: Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2007, 5:475-482.
  • [34]Bogdanov VY, Balasubramanian V, Hathcock J, et al.: Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 2003, 9:458-462.
  • [35]Sen P, Gopalakrishnan R, Kothari H, et al.: Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection. Blood 2011, 117:3199-3208.
  • [36]Gu JM, Katsuura Y, Ferrell GL, Grammas P, Esmon CT: Endotoxin and thrombin elevate rodent endothelial cell protein C receptor mRNA levels and increase receptor shedding in vivo. Blood 2000, 95:1687-1693.
  • [37]Keven K, Elmaci S, Sengul S, et al.: Soluble endothelial cell protein C receptor and thrombomodulin levels after renal transplantation. Int Urol Nephrol 2010, 42:1093-1098.
  • [38]Bash LD, Erlinger TP, Coresh J, et al.: Inflammation, hemostasis and the risk of kydney function decline in the atherosclerosis risk in communities (ARIC) Study. Am J Kidney Dis 2009, 53:596-605.
  文献评价指标  
  下载次数:5次 浏览次数:21次