HPA-1 and HPA-3 Polymorphisms of the Platelet Fibrinogen Receptor and Coronary Artery Disease and Myocardial Infarction

Summary

Platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa) plays a fundamental role in atherothrombosis. The human platelet antigen (HPA) -1 and the HPA-3 are the most extensively studied polymorphisms of GPIIIa and GPIIb, respectively. This study was designed to test, in a large population, the hypothesis that these polymorphisms represent a risk factor for the occurrence of coronary artery disease (CAD) and myocardial infarction (MI).

Consecutive, angiographically examined patients with significant coronary stenoses but without symptoms or signs of old or acute MI constituted the group with CAD (CAD, n = 998) and those with old or acute MI constituted the group with MI (MI, n = 793). As controls served subjects, matched with patients for age and sex, with neither angiographic CAD nor symptoms or signs of MI (matched controls [MC], n = 340) as well as a group of blood donors without cardiac symptoms or signs of CAD (BD, n = 104). Genotype distribution was similar across the groups; HPA-1a/a: HPA-1a/b: HPA-1b/b was 75.0%: 22.1%: 2.9% in BD, 72.6%: 24.7%: 2.6% in MC, 70.5%: 26.8%: 2.7% in CAD, and 70.7%: 26.4%: 2.9% in MI; HPA-3a/a: HPA-3a/b: HPA-3b/b was 39.4%: 40.4%: 20.2% in BD, 33.5%: 50.0%: 16.5% in MC, 35.0%: 46.4%: 17.0% in CAD, and 37.1%: 48.0%: 16.5% in MI. There was no interaction between these polymorphisms, nor between each of these polymorphisms and other risk factors.

Thus, the HPA-1 and HPA-3 polymorphisms are neither separately nor in concert associated with any measurable increase of the risk for CAD or MI in angiographically evaluated subjects.

Keywords

Coronary artery disease - myocardial infarction - platelets - fibrinogen receptor - genetics

• References

• 1 Narins CR, Topol EJ. Attention shifts to the white clot. Lancet 1997; 350 (Suppl. III): 2.
• 2 Handin RI. Platelets and coronary artery disease. N Engl J Med 1996; 334: 1126-7.
• 3 Wu KK. Platelet activation mechanisms and markers in arterial thrombosis. J Intern Med 1996; 239: 17-34.
• 4 Platelet activation and arterial thrombosis. Report of a meeting of Physicians and Scientists, University of Texas Health Science Center at Houston and Texas Heart Institute, Houston. Lancet 1994; 344: 991-5.
• 5 Gawaz M, Neumann FJ, Schömig A. Evaluation of platelet membrane glycoproteins in coronary artery disease: consequences for diagnosis and therapy. Circulation 1999; 99: E1-E11.
• 6 Calvette JJ. On the structure and function of platelet integrin α_IIbβ₃, the fibrinogen receptor. Proc Soc Exp Biol Med 1995; 208: 346-60.
• 7 Lyman S, Aster RH, Visentin GP, Newman PJ. Polymorphism of human platelet membrane glycoprotein IIb associated with the Baka/Bakb alloantigen system. Blood 1990; 75: 2343-8.
• 8 Nurden AT. Polymorphisms of human platelet membrane glycoproteins: structure and clinical significance. Thromb Haemost 1995; 74: 345-51.
• 9 Corral J, Gonzalez-Conejero R, Rivera J, Iniesta JA, Lozano ML, Vicente V. HPA-1 genotype in arterial thrombosis – role of HPA-1b polymorphism in platelet function. Blood Coagul Fibrinolysis 1997; 08: 284-90.
• 10 Meiklejohn DJ, Urbaniak SJ, Greaves M. Platelet glycoprotein IIIa polymorphism HPA 1b (PlA2): no association with platelet fibrinogen binding. Br J Haematol 1999; 105: 664-6.
• 11 Feng D, Lindpaintner K, Larson MG, Rao VSO, Donnell CJ, Lipinska I, Schmitz C, Sutherland PA, Silbershatz HD, Agostino RB, Muller JE, Myers RH, Levy D, Tofler GH. Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 1999; 19: 1142-7.
• 12 Goodall AH, Curzen N, Panesar M, Hurd C, Knight CJ, Ouwehand WH, Fox KM. Increased binding of fibrinogen to glycoprotein IIIa-Proline33 (HPA-1b, PlA2, Zwb) positive platelets in patients with cardiovascular disease. Eur Heart J 1998; 20: 742-7.
• 13 Lasne D, Krenn M, Pingault V, Arnaud E, Fiessinger JN, Aiach M, Rendu F. Interdonor variability of platelet response to thrombin receptor activation: influence of PlA2 polymorphism. Br J Haematol 1997; 99: 801-7.
• 14 Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-4.
• 15 Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ. Association of the platelet PlA polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bβ 448 polymorphism with myocardial infarction and extent of coronary artery disease. Circulation 1997; 96: 1424-31.
• 16 Gardemann A, Humme J, Stricker J, Nguyen QD, Katz N, Philipp M, Tillmanns H, Hehrlein FW, Rau M, Haberbosch W. Association of the platelet glycoprotein IIIa PlA1/A2 gene polymorphism to coronary artery disease but not to nonfatal myocardial infarction in low risk patients. Thromb Haemost 1998; 80: 214-7.
• 17 Garcia-Ribes M, Gonzalez-Lamuno D, Hernandez-Estefania R, Colman T, Pocovi M, Delgado-Rodriguez M, Garcia-Fuentes M, Revuelta JM. Polymorphism of the platelet glycoprotein IIIa gene in patients with coronary stenosis. Thromb Haemost 1998; 79: 1126-9.
• 18 Zotz RB, Winkelmann BR, Nauck M, Giers G, Maruhn-Debowski B, Marz W, Scharf RE. Polymorphism of platelet membrane glycoprotein IIIa: human platelet antigen 1b (HPA-1b/PlA2) is an inherited risk factor for premature myocardial infarction in coronary artery disease. Thromb Haemost 1998; 79: 731-5.
• 19 Anderson JL, King GJ, Bair TL, Elmer SP, Muhlestein JB, Habashi J, Carlquist JF. Associations between a polymorphism in the gene encoding glycoprotein IIIa and myocardial infarction or coronary artery disease. J Am Coll Cardiol 1999; 33: 727-33.
• 20 Ridker PM, Hennekens CH, Scmitz C, Stampfer MJ, Lindpaintner K. PlA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997; 349: 385-8.
• 21 Samani NJ, Lodwick D. Glycoprotein IIIa polymorphism and risk of myocardial infarction. Cardiovasc Res 1997; 33: 693-7.
• 22 Herrmann SM, Poirier O, Marques-Vidal P, Evans A, Arveiler D, Luc G, Emmerich J, Cambien F. The Leu33/Pro polymorphism (PlA1/PlA2) of the glycoprotein IIIa (GPIIIa) receptor is not related to myocardial infarction in the ECTIM Study. Etude Cas-Temoins de l’Infarctus du Myocarde. Thromb Haemost 1997; 77: 1179-81.
• 23 Durante-Mangoni E, Davies GJ, Ahmed N, Ruggiero G, Tuddenham EG. Coronary thrombosis and the platelet glycoprotein IIIA gene PLA2 polymorphism. Thromb Haemost 1998; 80: 218-9.
• 24 Scaglione L, Bergerone S, Gaschino G, Imazio M, Maccagnani A, Gambino R, Cassader M, Di Leo M, Macchia G, Brusca A, Pagano G, Cavallo-Perin P. Lack of relationship between the P1A1/P1A2 polymorphism of platelet glycoprotein IIIa and premature myocardial infarction. Eur J Clin Invest 1998; 28: 385-8.
• 25 Carlsson LE, Greinacher A, Spitzer C, Walther R, Kessler C. Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with and increased risk for stroke. Stroke 1997; 28: 1392-5.
• 26 Hato T, Minamoto Y, Fukuyama T, Fujita S. Polymorphisms of HPA-1 through 6 on platelet membrane glycoprotein receptors are not a genetic risk factor for myocardial infarction in the Japanese population. Am J Cardiol 1997; 80: 1222-4.
• 27 Sperr WR, Huber K, Roden M, Janisiw M, Lang T, Graf S, Maurer G, Mayr WR, Panzer S. Inherited platelet glycoprotein polymorphisms and a risk for coronary heart disease in young central Europeans. Thromb Res 1998; 90: 117-23.
• 28 Green FR, Watkins H. Genetic association studies in coronary disease: the case of GPIIb-IIIa polymorphisms. Eur Heart J 1999; 20: 706-8.
• 29 Joint International Society and Federation of Cardiology/World Health Organization Task Force. Nomenclature and criteria for diagnosis of ischemic heart disease. Circulation 1979; 59: 607-9.
• 30 World Health Organisation Study Group. Diabetes mellitus. WHO Tech Rep Ser 1985; 727: 1-104.
• 31 Guidelines Subcommittee. 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999; 17: 151-83.
• 32 Unkelbach K, Kalb R, Santoso S, Kroll H, Mueller-Eckhardt C, Kiefel V. Genomic RFLP typing of human platelet alloantigens Ww(PlA), Ko, Bak and Br (HPA-1, 2, 3, 5). Br J Haematol 1995; 89: 169-76.
• 33 Steffensen R, Kaczan E, Varming K, Jersild C. Frequency of platelet-specific alloantigens in a Danish population. Tissue Antigens 1996; 48: 93-6.
• 34 Kekomaki S, Partanen J, Kekomaki R. Platelet alloantigens HPA-1, -2, -3, -5 and -6b in Finns. Transfus Med 1995; 05: 193-8.
• 35 Simsek S, Faber NM, Bleeker PM, Vlekke ABJ, Huiskess E, Goldschmeding R, von dem Borne AEGK. Determination of human platelet antigen frequencies in the Dutch population by immunophenotyping and DNA (allele-specific restriction enzyme) analysis. Blood 1993; 81: 835-40.
• 36 Walter DH, Schächinger V, Elsner M, Dimmeler S, Zeiher AM. Platelet glycoprotein IIIa polymorphisms and risk of coronary stent thrombosis. Lancet 1997; 350: 1217-9.
• 37 Kastrati A, Gawaz M, Koch W, Kettling C, Mehilli J, Schömig K, von Beckerath N, Koetz F, Seidl H, Elezi S, Schömig A. Patients homozygous for the PlA2 allele coding for platelet glycoprotein IIIa are at increased risk for stent vessel thrombosis after coronary stent placement (abstract). Eur Heart J 1998; 19 (Suppl): 360.
• 38 Kastrati A, Schömig A, Seyfarth M, Koch W, Elezi S, Böttiger C, Mehilli J, Schömig K, von Beckerath N. PlA polymorphism of platelet glycoprotein IIIa and risk of restenosis after coronary stent placement. Circulation 1999; 99: 1005-10.
• 39 Böttiger C, Kastrati A, Koch W, Mehilli J, von Beckerath N, Dirschinger J, Gawaz M, Schömig A. Polymorphism of platelet glycoprotein IIb and risk of thrombosis and restenosis after coronary stent placement. Am J Cardiol 1999; 99: 987-91.