Journal of Thrombosis and Thrombolysis

, Volume 13, Issue 1, pp 13–19

Platelet Glycoprotein Ibα Receptor Polymorphisms and Recurrent Ischaemic Events in Acute Coronary Syndrome Patients

  • Dermot Kenny
  • Clare Muckian
  • Desmond J. Fitzgerald
  • Christopher P. Cannon
  • Denis C. Shields
Article

Abstract

Aims: To examine the relationship between polymorphisms in the platelet receptor glycoprotein (GP) Ibα and recurrent ischaemic events, and assess their impact on response to anti-platelet treatment.

Methods and Results: 1014 patients presenting with unstable coronary syndrome were recruited from the OPUS-TIMI 16 clinical trial of the platelet GPIIb/IIIa antagonist, orbofiban. The subjects were genotyped for two polymorphisms in the gene for GPIbα. These were a T-5C polymorphism in the 5′ untranslated Kozak region of the GPIbα gene, and the variable number of tandem repeats (VNTR) in the macroglycopeptide region.

165 patients had events (recurrent ischaemia, urgent revascularisation, myocardial infarction (MI), stroke and death). There was no effect of the number of −5C alleles on composite endpoint frequency among Caucasian subjects (test for trend, p = 0.47). However, MI risk increased with the number of −5C alleles carried, with MI occurring in 2.3% of patients with the −5T/−5T genotype, 5.0% of −5T/−5C, and 16.7% of −5C/−5C (p < 0.01). The effect of treatment on MI outcome was not significantly modified by genotype (test for interaction, p = 0.10). The overall risk of bleeding was not strongly influenced by either the −5C or the VNTR polymorphisms.

Conclusion: In an unstable coronary syndrome population the T-5C polymorphism in GPIbα influences risk of subsequent MI.

platelets genetics myocardial infarction ischaemia glycoproteins 

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References

  1. 1.
    Kenny D, Jónsson OG, Morateck PA, Montgomery RR. Naturally occurring mutations in glycoprotein Ibα that result in defective ligand binding and synthesis of a truncated protein. Blood 1998;92:175–183.Google Scholar
  2. 2.
    van Zanten GH, de Graaf S, Slootweg PJ, et al. Increased platelet deposition on atherosclerotic coronary arteries. J Clin Invest 1994;93:615–632.Google Scholar
  3. 3.
    de Feyter PJ, Ozaki Y, Baptista J, et al. Ischemia-related lesion characteristics in patients with stable or unstable angina. Circulation 1995;92:1408–1413.Google Scholar
  4. 4.
    Davies MJ, Thomas AC. Plaque fissuring-the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363–373.Google Scholar
  5. 5.
    Kobe B, Deisenhofer J. The leucine-rich repeat: a versatile binding motif. Trends in Biochem Sci 1994;19:415–421.Google Scholar
  6. 6.
    López JA, Ludwig EH, McCarthy BJ. Polymorphism of human glycoprotein Iba results from a variable number of tandem repeats of a 13-amino acid sequence in the mucin-like macroglycopeptide region. J Biol Chem 1992;267:10055–10061.Google Scholar
  7. 7.
    Kenny D, Newman PJ, Morateck PA, Montgomery RR. A dinucleotide deletion in glycoprotein Ibα results in defective membrane anchoring and circulating soluble glyco-protein Ibα in a novel form of Bernard-Soulier syndrome. Blood 1997;90:2626–2633.Google Scholar
  8. 8.
    Afshar-Kharghan V, Khoshnevis-Asl M, Hopkins P, Lopez JA. Polymorphims of the platelet glycoprotein (GP) Ibα 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
  9. 9.
    Corral J, Lozano ML, Gonzalez-Conejero R, et al. A common polymorphism flanking the ATG codon of GPIb alpha does not affect expression and is not a major risk factor for arterial thrombosis. Thromb Haem 2000;83:23–28.Google Scholar
  10. 10.
    Murata M, Furihata K, Ishida F, Russell SR, Ware J, Ruggeri ZM. Genetic and structural characterization of an amino acid dimorphisms in glycoprotein Ibα involved in platelet transfusion refractoriness. Blood 1992;79:3086.Google Scholar
  11. 11.
    Sperr WR, Huber K, Roden M, et al. Inherited platelet glycoprotein polymorphisms and a risk for coronary heart disease in young central Europeans. Thrombosis Research 1998;90:117–123.Google Scholar
  12. 12.
    Murata M, Matsubara Y, Kawano K, et al. Coronary artery disease and polymorphisms in a receptor mediating shear stress-dependent platelet activation. Circulation 1997;96:3281–3286.Google Scholar
  13. 13.
    Carter AM, Catto AJ, Bamford JM, Grant PJ. Platelet GP IIIa Pla and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. Arterioscler Throm Vasc Biol 1998;18:1124–1131.Google Scholar
  14. 14.
    Gonzalez-Conejero R, Lozano ML, Rivera J, et al. Polymorphisms of platelet membrane glycoprotein Ibα associated with arterial thrombotic disease. Blood 1998;92:2771–2776.Google Scholar
  15. 15.
    Cannon CP, McCabe CH, Wilcox RG, et al., for the OPUS-TIMI 16 Investigators: oral glycoprotein IIb/IIIa inhibition with orofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000;102:149–156.Google Scholar
  16. 16.
    Ferguson JJ. Meeting highlights. Circulation 1999;100: 570–575.Google Scholar
  17. 17.
    Hillmann A, Shields D, Fitzgerald DJ, Kenny D. Polymorphisms in GPIb alpha are not associated with adverse outcomes in primigravidae. Journal of Obstetrics and Gynaecology 2000;20:250–255.Google Scholar
  18. 18.
    Morton NE. Genetic structure of forensic populations. Proceedings of the National Academy of Science 1992;89:2556–2560.Google Scholar
  19. 19.
    Bacanu SA, Devlin B, Roeder K. The poer of genomic control. Am J Hum Genet 2000;66:1933–1944.Google Scholar
  20. 20.
    Ishida F, Furihata K, Ishida K, et al. The largest variant of platelet glycoprotein Ibα has four tandem repeats of 13 amino acids in the macroglycopeptide region and a genetic linkage with methionine 145. Blood 1995;86:1357–1360.Google Scholar
  21. 21.
    O'Neill WW, Serruys P, Knudtson M, et al. Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. EXCITE trial investigators. N Engl J Med 2000;342:1316–1324.Google Scholar
  22. 22.
    Graham I, Mulcahy R, Hickey N, O'Neill W, Daly L. Natural history of coronary heart disease: a study of 586 men surviving an initial acute attack. Am Heart Journal 1983;105:249–257.Google Scholar
  23. 23.
    Bray PF. Integrin polymorphisms as risk factors for thrombosis. Thromb Haem 1999;82:337–344.Google Scholar
  24. 24.
    Nordt TK, Peter K, Ruef J, Kubler W, Bode C. Plasminogen activator inhibitor type-1 (PAI-1) and its role in cardiovascular disease. Throb Haem 1999;82(Suppl 1):14–18.Google Scholar
  25. 25.
    Murata M, Kawano K, Matsubara Y, Ishikawa K, Watanabe K, Ikeda Y. Genetic polymorphisms and risk of coronary artery disease. Semin Thromb Hemost 1998;24:245–250.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Dermot Kenny
    • 1
  • Clare Muckian
    • 2
  • Desmond J. Fitzgerald
    • 3
  • Christopher P. Cannon
    • 4
  • Denis C. Shields
    • 3
  1. 1.Department of Clinical PharmacologyDublin 2Ireland
  2. 2.Royal College of Surgeons in IrelandSurgen Ltd.Dublin 2Ireland
  3. 3.Department of Clinical Pharmacology and Surgen Ltd.Royal College of Surgeons in IrelandDublin 2Ireland
  4. 4.Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Emergency MedicineWashington Hospital CenterWashingtonUSA

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