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Cited by 61Blood Coagulation and Thrombosis MechanismsGenetic Associations and EpidemiologyComplement system in diseases

PROC,PROCR andPROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study

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REINER, A.P., CARTY, C.L., JENNY, N.S., NIEVERGELT, C., CUSHMAN, M., STEARNS‐KUROSAWA, D.J., KUROSAWA, S., KULLER, L.H. +1 more·2008·Journal of Thrombosis and Haemostasis
DOI 10.1111/j.1538-7836.2008.03118.xPMC PMC2856703
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Abstract

Background and objectives Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging-related disorders. Methods Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of incident clinical outcomes [coronary heart disease (CHD), stroke, and mortality] in 4547 participants during follow-up. Secondarily, we explored associations between plasma protein C, protein S and sEPCR levels and other candidate genes involved in thrombosis, inflammation, and aging. Results The PROCR Ser219Gly polymorphism (rs867186) was strongly associated with higher sEPCR levels, explaining 75% of the phenotypic variation. The PROCR Ser219Gly variant was also associated with higher levels of circulating protein C antigen. An IL10 polymorphism was associated with higher free protein S levels. The minor alleles of PROC rs2069901 and PROS1 rs4857343 were weakly associated with lower protein C and free protein S levels, respectively. There was no association between PROCR Ser219Gly and risk of CHD, stroke, or mortality. The minor allele of another common PROCR tagSNP, rs2069948, was associated with lymphoid PROCR mRNA expression and with increased risk of incident stroke and all-cause mortality, and decreased healthy survival during follow-up. Conclusions A common PROCR variant may be associated with decreased healthy survival in older adults. Additional studies are warranted to establish the role of PROCR variants in ischemic and aging-related disorders.

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Research works printed but not linked: 35

  1. [1]Dahlback B Villoutreix BO The anticoagulant protein C pathway FEBS Lett 2005 579 3310 6 15943976
  2. [2]Mosnier LO Zlokovic BV Griffin JH The cytoprotective protein C pathway Blood 2007 109 3161 72 17110453
  3. [3]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 10 15304035
  4. [4]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 8 14576048
  5. [5]Souto JC Almasy L Borrell M Gari M Martinez E Mateo J Stone WH Blangero J Fontcuberta J Genetic determinants of hemostasis phenotypes in Spanish families Circulation 2000 101 1546 51 10747348
  6. [6]Vossen CY Hasstedt SJ Rosendaal FR Callas PW Bauer KA Broze GJ Hoogendoorn H Long GL Scott BT Bovill EG Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C-deficient family J Thromb Haemost 2004 2 242 7 14995985
  7. [7]Almasy L Soria JM Souto JC Coll I Bacq D Faure A Mateo J Borrell M Munoz X Sala N Stone WH Lathrop M Fontcuberta J Blangero J Genetic Analysis of Idiopathic Thrombophilia project A quantitative trait locus influencing free plasma protein S levels on human chromosome 1q: results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project Arterioscler Thromb Vasc Biol 2003 23 508 11 12615682
  8. [8]Buil A Soria JM Souto JC Almasy L Lathrop M Blangero J Fontcuberta J Protein C levels are regulated by a quantitative trait locus on chromosome 16: results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project Arterioscler Thromb Vasc Biol 2004 24 1321 5 15142863
  9. [9]Spek CA Koster T Rosendaal FR Bertina RM Reitsma PH Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk Arterioscler Thromb Vasc Biol 1995 15 214 8 7749828
  10. [10]Aiach M Nicaud V Alhenc-Gelas M Gandrille S Arnaud E Amiral J Guize L Fiessinger JN Emmerich J Complex association of protein C gene promoter polymorphism with circulating protein C levels and thrombotic risk Arterioscler Thromb Vasc Biol 1999 19 1573 6 10364092
  11. [11]Ireland H Konstantoulas CJ Cooper JA Hawe E Humphries SE Mather H Goodall AH Hogwood J Juhan-Vague I Yudkin JS di Minno G Margaglione M Hamsten A Miller GJ Bauer KA Kim YT Stearns-Kurosawa DJ Kurosawa S EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro Atherosclerosis 2005 183 283 92 15921688
  12. [12]Diehr P Patrick DL Bild DE Burke GL Williamson JD Predicting future years of healthy life for older adults J Clin Epidemiol 1998 51 343 53 9539891
  13. [13]Cushman M Cornell ES Howard PR Bovill EG Tracy RP Laboratory methods and quality assurance in the Cardiovascular Health Study Clin Chem 1995 41 264 270 7874780
  14. [14]Sakkinen PA Cushman M Psaty BM Kuller LH Bajaj SP Sabharwal AK Boineau R Macy E Tracy RP Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort Thromb Haemost 1998 80 134 9 9684799
  15. [15]Stearns-Kurosawa DJ Swindle K D’Angelo A Della Valle P Fattorini A Caron N Grimaux M Woodhams B Kurosawa S Plasma levels of endothelial protein C receptor respond to anticoagulant treatment Blood 2002 Jan 15 99 2 526 30 11781234
  16. [16]Carlson CS Eberle MA Rieder MJ Yi Q Kruglyak L Nickerson DA Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium Am J Hum Genet 2004 74 106 120 14681826 PMC1181897
  17. [17]Lange LA Reiner AP Carty CA Jenny NS Cushman M Lange EM Common genetic determinants of plasma fibrin D-dimer concentration in older European- and African-American adults J Thromb Haemostas 2008 6 654 659 18208536
  18. [18]Purcell S Neale B Todd-Brown K Thomas L Ferreira MA Bender D Maller J Sklar P de Bakker PI Daly MJ Sham PC PLINK: a tool set for whole-genome association and population-based linkage analyses Am J Hum Genet 2007 81 559 75 17701901 PMC1950838
  19. [19]Lin DY Haplotype-based association analysis in cohort studies of unrelated individuals Genet Epidemiol 2004 26 255 264 15095385
  20. [20]Conneely KN Boehnke M So many correlated tests, so little time! Rapid adjustment of p-values for multiple correlated tests Am J Hum Genet 2007 81 1158 68 17966093 PMC2276357
  21. [21]Storey JD Tibshirani R Statistical significance for genomewide studies Proc Natl Acad Sci U S A 2003 100 9440 5 12883005 PMC170937
  22. [22]Stranger BE Forrest MS Clark AG Minichiello MJ Deutsch S Lyle R Hunt S Kahl B Antonarakis SE Tavare S Deloukas P Dermitzakis ET Genome-wide associations of gene expression variation in humans PLoS Genet 2005 1 e78 16362079 PMC1315281
  23. [23]Scopes D Berg LP Krawczak M Kakkar VV Cooper DN Polymorphic variation in the human protein C (PROC) gene promoter can influence transcriptional efficiency in vitro Blood Coagul Fibrinolysis 1995 6 317 21 7548679
  24. [24]de Wolf CJ Cupers RM Bertina RM Vos HL The constitutive expression of anticoagulant protein S is regulated through multiple binding sites for Sp1 and Sp3 transcription factors in the protein S gene promoter J Biol Chem 2006 281 17635 43 16672217
  25. [25]Hall AJ Peake IR Winship PR Regulation of the human protein S gene promoter by liver enriched transcription factors Br J Haematol 2006 135538 46 17061980
  26. [26]Duchemin J Gandrille S Borgel D Feurgard P Alhenc-Gelas M Matheron C Dreyfus M Dupuy E Juhan-Vague I Aiach M The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency Blood 1995 86 3436 43 7579448
  27. [27]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 35 16409473
  28. [28]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 9218519 PMC508205
  29. [29]Mollica LR Crawley JT Liu K Rance JB Cockerill PN Follows GA Landry JR Wells DJ Lane DA Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene Blood 2006 108 1251 9 16627757
  30. [30]Medina P Navarro S Estelles A Vaya A Woodhams B Mira Y Villa P Migaud-Fressart M Ferrando F Aznar J Bertina RM Espana 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 11 15116250
  31. [31]Cheng T Liu D Griffin JH Fernandez JA Castellino F Rosen ED Fukudome K Zlokovic BV Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective Nat Med 2003 9 338 42 12563316
  32. [32]Sturn DH Kaneider NC Feistritzer C Djanani A Fukudome K Wiedermann CJ Expression and function of the endothelial protein C receptor in human neutrophils Blood 2003 102 1499 505 12714492
  33. [33]Feistritzer C Mosheimer BA Sturn DH Riewald M Patsch JR Wiedermann CJ Endothelial protein C receptor-dependent inhibition of migration of human lymphocytes by protein C involves epidermal growth factor receptor J Immunol 2006 176 1019 25 16393989
  34. [34]Kerschen EJ Fernandez JA Cooley BC Yang XV Sood R Mosnier LO Castellino FJ Mackman N Griffin JH Weiler H Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C J Exp Med 2007 204 2439 48 17893198 PMC2118455
  35. [35]Zheng X Li W Song Y Hu Y Ferrell GL Esmon NL Esmon CT Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia J Thromb Haemost 2007 5 1394 400 17445091

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Authors
REINER, A. P., CARTY, C. L., JENNY, N. S., NIEVERGELT, C., CUSHMAN, M., STEARNS‐KUROSAWA, D. J., KUROSAWA, S., KULLER, L. H., & LANGE, L. A.
Affiliations
  • University of Washington (US)
  • University of Vermont (US)
  • University of California San Diego (US)
  • Boston University (US)
  • University of Pittsburgh (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
REINER, A.P.
ORCID
Venue
Journal of Thrombosis and Haemostasis
Publisher
Elsevier BV
Published
2008-10
Volume
6
Issue
10
Pages
1625-1632
ISSN
1538-7836 (ISSN-L)
DOI
10.1111/j.1538-7836.2008.03118.x
PMC
PMC2856703
OpenAlex
W2089298781
Cited by
61
References
0
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 5 · 2015: 2 · 2014: 6 · 2013: 3 · 2012: 4
FWCI
3.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Thrombosis and Haemostasis (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Johns Hopkins University
  • National Institutes of Health (n01hc085082-026, n01hc085081-021, n01hc085079-024, n01hc015103-009, n01hc085084-005, n01hc085085-011, n01hc085083-027, n01hc085080-026, n01hg065403-000, n01hv48195-5-0-1, n01hc085086-022, n01hc55222-0-0-0, n01hc035129-010)
  • National Institute on Aging (U19AG023122)
  • National Heart, Lung, and Blood Institute (N01-HC-85081, N01-HV-48195, N01 HC085086, N01HC-85083, U01 HL-66682, N01 HC085079, N01 HC085083, N01HC85082, N01 HC85086, N01 HC085080, N01 HC035129, N01HC85080, N01 HC015103, N01 HV048195, N01 HC55222, N01 HC085085, R01HL071862, U01HL066682, N01HC085082, U01HL080295, N01 HC055222, K08HL080293, N01 HC085081, N01 HC085084, N01-HC85079)
  • National Human Genome Research Institute (N01 HG065403)
Topics
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Keywords
PROC, protein C receptor, protein S, protein C, anticoagulant pathway, genetic polymorphism, coronary artery disease, stroke, mortality, older adults, IL-10, thrombosis, aging, cardiovascular risk
MeSH terms
Endothelial Protein C Receptor, Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Coronary Disease, Female, Humans, Inflammation, Male, Middle Aged, Mortality, Polymorphism, Genetic, Protein C, Receptors, Cell Surface, Risk, Thrombosis, Antigens, CD, Protein S, Blood Coagulation Factor Inhibitors, Stroke

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