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The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists

The Pharmacogenomics Journal volume 2, pages 182–190 (2002)Cite this article

Abstract

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbα; platelet ligands β-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (χ2 = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.

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References

  1. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U . Genetic susceptibility to death from coronary heart disease in a study of twins N Engl J Med 1994 330: 1041–1046

    Article  CAS  Google Scholar 

  2. Lane DA, Grant PJ . Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease Blood 2000 95: 1517–1532

    CAS  PubMed  Google Scholar 

  3. Cannon CP, McCabe CH, Wilcox RG, Langer A, Caspi A, Benink P et al . Oral glycoprotein IIb/IIIa inhibition with orofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial Circulation 2000 102: 149–156

    Article  CAS  Google Scholar 

  4. O'Connor FF, Shields DC, Fitzgerald A, Cannon CP, Braunwald E, Fitzgerald DJ . Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes Blood 2001 98(12): 3256–3260

    Article  Google Scholar 

  5. Kenny D, Muckian C, Fitzgerald DJ, Cannon CP, Shields DC . Platelet glycoprotein Ib alpha receptor polymorphisms and recurrent ischaemic events in acute coronary syndrome patients J Thrombos. Thrombolys 2002 13: 13–19

    Article  CAS  Google Scholar 

  6. Keavney B, McKenzie C, Parish S, Palmer A, Clark S, Youngman L et al . Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators Lancet 2000 355: 434–442

    Article  CAS  Google Scholar 

  7. Cannon C, McCabe CH, Wilcox RG, Langer A, Caspi A, Berink P et al . Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial Circulation 2000 102: 149–156

    Article  CAS  Google Scholar 

  8. Ardissino D, Mannucci PM, Merlini PA, Duca F, Fetiveau R, Tagliabue L et al . Prothrombotic genetic risk factors in young survivors of myocardial infarction Blood 1999 94: 46–51

    CAS  PubMed  Google Scholar 

  9. Afshar-Kharghan V, Khoshnevis-Asl M, Hopkins P, Lopez JA . Polymorphisms of the platelet glycoprotein (GP) Ibγ kozak sequence determines the surface level of the GP-Ib-IX-V complex and risk for early myocardial infarction Blood 1998 92: A2887

    Google Scholar 

  10. Croft SA, Hampton KK, Daly ME, Ste RP eds Channer KS, Sarmai NJ et al . Kozak sequence polymorphism in the platelet GPIb gene is not associated with the risk of myocardial infarction Blood 2000 95: 2183

    CAS  PubMed  Google Scholar 

  11. Keightley AM, Lam YM, Brady JN, Cameron CL, Lillicrap D . Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF:Ag levels: identification of three novel single nucleotide polymorphisms in the vWF gene promoter Blood 1999 93: 4277–4283

    CAS  PubMed  Google Scholar 

  12. Montalescot G, Philippe F, Ankri A, Vicaut E, Bearez E, Poulard JE et al . Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease: beneficial effects of enoxaparin. French Investigators of the ESSENCE Trial Circulation 1998 98: 294–299

    Article  CAS  Google Scholar 

  13. Heywood DM, Ossei-Gerning N, Grant PJ . Two novel polymorphisms of the von Willebrand factor gene promoter polymorphism and association with ischaemic heart disease Thromb Haemost 1997 77 (Suppl): S375

    Google Scholar 

  14. Kritzik M, Savage B, Nugent DJ, Santoso S, Ruggeri ZM, Kunicki TJ . Nucleotide polymorphisms in the alpha2 gene define multiple alleles that are associated with differences in platelet alpha2 beta1 density Blood 1998 92: 2382–2383

    CAS  PubMed  Google Scholar 

  15. Moshfegh K, Wuillemin WA, Redondo M, Lammle B, Beer JH, Liechti-Gallati S et al . Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a case-control study Lancet 1999 353: 351–354

    Article  CAS  Google Scholar 

  16. Jacquelin B, Tarantino MD, Kritzik M, Rozenshteyn D, Koziol JA, Nurden AT et al . Allele-dependent transcriptional regulation of the human integrin alpha2 gene Blood 2001 97: 1721–1726

    Article  CAS  Google Scholar 

  17. Di Paola J, Federici AB, Mannucci PM, Canciani MT, Kritzik M, Kunicki TJ et al . Low platelet alpha2beta1 levels in type I von Willebrand disease correlate with impaired platelet function in a high shear stress system Blood 1999 93: 3578–3582

    CAS  PubMed  Google Scholar 

  18. Francis SE, Camp NJ, Dewberry RM, Gunn J, Syrris P, Carter ND et al . Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease Circulation 1999 99: 861–866

    Article  CAS  Google Scholar 

  19. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA et al . Interleukin-1 polymorphisms associated with increased risk of gastric cancer Nature 2000 404: 398–402

    Article  CAS  Google Scholar 

  20. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S et al . The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis J Clin Invest 1998 102: 1369–1376

    Article  CAS  Google Scholar 

  21. Rauramaa R, Vaisanen SB, Luong LA, Schmidt-Trucksass A, Penttila IM, Bouchard C et al . Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis Arterioscler Thromb Vasc Biol 2000 20: 2657–2662

    Article  CAS  Google Scholar 

  22. Wenzel K, Felix S, Kleber FX, Brachold R, Menke T, Schattke S et al . E-selectin polymorphism and atherosclerosis: an association study Hum Mol Genet 1994 3: 1935–1937

    Article  CAS  Google Scholar 

  23. Ye SQ, Usher D, Virgil D, Zhang LQ, Yochim SE, Gupta R . A PstI polymorphism detects the mutation of serine128 to arginine in CD 62E gene—a risk factor for coronary artery disease J Biomed Sci 1999 6: 18–21

    CAS  PubMed  Google Scholar 

  24. Herrmann SM, Ricard S, Nicaud V, Mallet C, Evans A, Ruidavets JB et al . The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction Hum Mol Genet 1998 7: 1277–1284

    Article  CAS  Google Scholar 

  25. Kee F, Morrison C, Evans AE, McCrum E, McMaster D, Dallongeville J et al . Polymorphisms of the P-selectin gene and risk of myocardial infarction in men and women in the ECTIM extension study Etude cas-temoin de l'infarctus myocarde. Heart 2000 84: 548–552

    CAS  PubMed  Google Scholar 

  26. Zhang B, Ye S, Herrmann S, Eriksson P, de MNaat M, Evans A et al . Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis Circulation 1999 99: 1788–1794

    Article  CAS  Google Scholar 

  27. Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Steinkasserer A et al . Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat Hum Genet 1993 91: 403–404

    Article  CAS  Google Scholar 

  28. Hillmann A, Shields D, Fitzgerald DJ, Kenny D . Polymorphisms in GPIb alpha are not associated with adverse outcomes in primigravidae J Obstetrics Gynaecol 2000 20: 250–255

    Article  CAS  Google Scholar 

  29. O'Connor F, Fitzgerald DJ, Murphy RP . An automated heteroduplex assay for the PlA polymorphism of glycoprotein IIb/IIIa, multiplexed with two prothrombotic genetic markers, factor V Leiden, and methylenetetrahyrofolate reductase Thromb Haemost 2000 83: 248–252

    Article  CAS  Google Scholar 

  30. Hoogendoorn B, Owen MJ, Oefner PJ, Williams N, Austin J, O'Donovan MC . Genotyping single nucleotide polymorphisms by primer extension and high performance liquid chromatography Hum Genet 1999 104: 89–93

    Article  CAS  Google Scholar 

  31. Morton NE . Genetic structure of forensic populations Proc Nat Acad Sci 1992 89: 2556–2560

    Article  CAS  Google Scholar 

  32. Bacanu SA, Devlin B, Roeder K . The power of genomic control Am J Hum Genet 2000 66: 1933–1944

    Article  CAS  Google Scholar 

  33. Hyndman ME, Bridge PJ, Warnica JW, Fick G, Parsons HG . Effect of heterozygosity for the methionine synthase 2756 A→G mutation on the risk for recurrent cardiovascular events Am J Cardiol 2000 86: 1144–1146 A9

    Article  CAS  Google Scholar 

  34. Holm J, Hillarp A, Zoller B, Erhardt L, Berntorp E, Dahlback B . Factor V Q506 (resistance to activated protein C) and prognosis after acute coronary syndrome Thromb Haemost 1999 81: 857–860

    Article  CAS  Google Scholar 

  35. Nyholt DR . Genetic case-control association studies—correcting for multiple testing Hum Genet 2001 109: 564–567

    Article  CAS  Google Scholar 

  36. McCarthy JJ, Hilfiker R . The use of single-nucleotide polymorphism maps in pharmacogenomics Nat Biotechnol 2000 18: 505–508

    Article  CAS  Google Scholar 

  37. Tukey JW . Some thoughts on clinical trials, especially problems of multiplicity Science 1977 198: 679–684

    Article  CAS  Google Scholar 

  38. weiss ST, Silverman EK, Palmer LJ . Case-control association studies in Pharmacogenomics The Pharmacogenomics Journal 2001 1: 157–158

    Article  CAS  Google Scholar 

  39. Bader JS . The relative power of SNPs and haplotype as genetic markers for association tests Pharmacogenomics 2001 2: 11–24

    Article  CAS  Google Scholar 

  40. Fellowes AP, Brennan SO, George PM . Identification and characterization of five new fibrinogen gene polymorphisms Ann N Y Acad Sci 2001 936: 536–541

    Article  CAS  Google Scholar 

  41. Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G et al . Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l'Infarctus du Myocarde Circulation 1996 93: 440–449

    Article  CAS  Google Scholar 

  42. Joos L, McIntyre L, Ruan J, Connett JE, Anthonisen NR, Weir TD et al . Association of IL-1beta and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers Thorax 2001 56: 863–866

    Article  CAS  Google Scholar 

  43. Topol EJ . The future of antiplatelet therapy: optimizing management in patients with acute coronary syndrome Clin Cardiol 2000 23 Suppl 6: VI–23–8

    Article  Google Scholar 

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Acknowledgements

We thank the OPUS-TIMI investigators for their effort in collecting samples for this study. We thank Fiona O'Connor for PLA2 genotyping and John Mullen for clinical database management. This work was funded by grants from the Higher Education Authority Ireland, and Searle Inc.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland

    D C Shields, D Kenny, C E Byrne & D J Fitzgerald

  2. Department of Epidemiology, Royal College of Surgeons in Ireland, Dublin, Ireland

    A P Fitzgerald

  3. Surgen Ltd, Royal College of Surgeons in Ireland, Dublin, Ireland

    D C Shields, P A O'Neill, C Muckian & B Moran

  4. Cardiovascular Division, TIMI Study Group, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

    C P Cannon

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  1. D C Shields
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Correspondence to D C Shields.

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Shields, D., Fitzgerald, A., O'Neill, P. et al. The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. Pharmacogenomics J 2, 182–190 (2002). https://doi.org/10.1038/sj.tpj.6500100

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  • DOI: https://doi.org/10.1038/sj.tpj.6500100

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