Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1142-1147
© 1999 American Heart Association, Inc.
Original Contributions |
Increased Platelet Aggregability Associated With Platelet GPIIIa PlA2 Polymorphism
The Framingham Offspring Study
From the Institute for Prevention of Cardiovascular Disease (D.F., I.L., G.H.T.), Beth Israel Deaconess Medical Center; Cardiovascular Division (K.L., V.S.R., C.S.), Brigham & Women's Hospital; the Department of Cardiology (K.L.), Children's Hospital, Harvard Medical School; National Heart, Lung and Blood Institute's Framingham Heart Study (M.G.L., C.J.O'D., P.A.S., D.L.); Statistics and Consulting Unit (H.S., R.B.D'A.), Department of Mathematics, Boston University; Cardiology Division (J.E.M.), University of Kentucky Medical Center; Department of Neurology (R.H.M.), Boston University.
Correspondence to Geoffrey H. Tofler, MD, Institute for Prevention of Cardiovascular Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, One Autumn St, 5th Floor, Boston, MA 02215. E-mail gtofler{at}bidmc.harvard.edu
Abstract—The platelet glycoprotein IIb/IIIa (GP IIb/IIIa) plays a pivotal role in platelet aggregation. Recent data suggest that the PlA2 polymorphism of GPIIIa may be associated with an increased risk for cardiovascular disease. However, it is unknown if there is any association between this polymorphism and platelet reactivity. We determined GP IIIa genotype and platelet reactivity phenotype data in 1422 subjects from the Framingham Offspring Study. Genotyping was performed using PCR-based restriction fragment length polymorphism analysis. Platelet aggregability was evaluated by the Born method. The threshold concentrations of epinephrine and ADP were determined. Allele frequencies of PlA1 and PlA2 were 0.84 and 0.16, respectively. The presence of 1 or 2 PlA2 alleles was associated with increased platelet aggregability as indicated by incrementally lower threshold concentrations for epinephrine and ADP. For epinephrine, the mean concentrations were 0.9 µmol/L (0.9 to 1.0) for homozygous PlA1, 0.7 mmol/L (0.7 to 0.9) for the heterozygous PlA1/PlA2, and 0.6 µmol/L (0.4 to 1.0) for homozygous PlA2 individuals, P=0.009. The increase in aggregability induced by epinephrine remained highly significant (P=0.007) after adjustment for covariates. For ADP-induced aggregation, the respective mean concentrations were 3.1 µmol/L (3.0 to 3.2), 3.0 µmol/L (2.9 to 3.2), and 2.8 µmol/L (2.4 to 3.3); P=0.19 after adjustment for covariates. Our findings indicate that molecular variants of the gene encoding GP IIIa play a role in platelet reactivity in vitro. Our observations are compatible with and provide an explanation for the reported association of the PlA2 allotype with increased risk for cardiovascular disease.
Key Words: platelets • genetics • glycoprotein • epinephrine
This article has been cited by other articles:
 |
|
 |
|
  J. E. Herrera-Galeano, D. M. Becker, A. F. Wilson, L. R. Yanek, P. Bray, D. Vaidya, N. Faraday, and L. C. Becker A Novel Variant in the Platelet Endothelial Aggregation Receptor-1 Gene Is Associated With Increased Platelet Aggregability Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1484 - 1490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Cerhan, S. M. Ansell, Z. S. Fredericksen, N. E. Kay, M. Liebow, T. G. Call, A. Dogan, J. M. Cunningham, A. H. Wang, W. Liu-Mares, et al. Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma Blood, December 15, 2007; 110(13): 4455 - 4463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Undas, K. E. Brummel-Ziedins, and K. G. Mann Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions Blood, March 15, 2007; 109(6): 2285 - 2292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. F. Bray, T. D. Howard, E. Vittinghoff, D. C. Sane, and D. M. Herrington Effect of genetic variations in platelet glycoproteins Ib{alpha} and VI on the risk for coronary heart disease events in postmenopausal women taking hormone therapy Blood, March 1, 2007; 109(5): 1862 - 1869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lim, S. Carballo, J. Cornelissen, Z. A. Ali, R. Grignani, S. Bellm, and S. Large Dose-Related Efficacy of Aspirin After Coronary Surgery in Patients With PlA2 Polymorphism (NCT00262275) Ann. Thorac. Surg., January 1, 2007; 83(1): 134 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Bushnell, P. Hurn, C. Colton, V. M. Miller, G. del Zoppo, M. S.V. Elkind, B. Stern, D. Herrington, G. Ford-Lynch, P. Gorelick, et al. Advancing the Study of Stroke in Women: Summary and Recommendations for Future Research From an NINDS-Sponsored Multidisciplinary Working Group Stroke, September 1, 2006; 37(9): 2387 - 2399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. V. Vijayan and P. F. Bray Molecular Mechanisms of Prothrombotic Risk Due to Genetic Variations in Platelet Genes: Enhanced Outside-In Signaling Through the Pro33 Variant of Integrin {beta}3. Experimental Biology and Medicine, May 1, 2006; 231(5): 505 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kubisz, J. Ivankova, P. Holly, J. Stasko, and J. Musia/l The Glycoprotein IIIa PLA1/A2 Polymorphism--A Defect Responsible for the Sticky Platelet Syndrome? Clinical and Applied Thrombosis/Hemostasis, January 1, 2006; 12(1): 117 - 119. [PDF]
|
|
|
|
 |
|
 S E Bojesen, S K Kjaer, E V S Hogdall, B L Thomsen, C K Hogdall, J Blaakaer, A Tybjaerg-Hansen, and B G Nordestgaard Increased risk of ovarian cancer in integrin {beta}3 Leu33Pro homozygotes Endocr. Relat. Cancer, December 1, 2005; 12(4): 945 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Yee, C. W. Sun, A. L. Bergeron, J.-f. Dong, and P. F. Bray Aggregometry detects platelet hyperreactivity in healthy individuals Blood, October 15, 2005; 106(8): 2723 - 2729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Weiss, L. A. Lester, J. E. Gern, R. L. Wolf, R. Parry, R. F. Lemanske, J. Solway, and C. Ober Variation in ITGB3 Is Associated with Asthma and Sensitization to Mold Allergen in Four Populations Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 67 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. V. Vijayan, Y. Liu, W. Sun, M. Ito, and P. F. Bray The Pro33 Isoform of Integrin {beta}3 Enhances Outside-in Signaling in Human Platelets by Regulating the Activation of Serine/Threonine Phosphatases J. Biol. Chem., June 10, 2005; 280(23): 21756 - 21762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Papp, V. Havasi, J. Bene, K. Komlosi, L. Czopf, E. Magyar, C. Feher, G. Feher, B. Horvath, Z. Marton, et al. Glycoprotein IIIA Gene (PlA) Polymorphism and Aspirin Resistance: Is There Any Correlation? Ann. Pharmacother., June 1, 2005; 39(6): 1013 - 1018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mikkelsson, M. Perola, and P. J. Karhunen Genetics of Platelet Glycoprotein Receptors: Risk of Thrombotic Events and Pharmacogenetic Implications Clinical and Applied Thrombosis/Hemostasis, April 1, 2005; 11(2): 113 - 125. [Abstract] [PDF]
|
|
|
|
|
|
C. S. Fox, M. G. Larson, D. Corey, D. Feng, K. Lindpaintner, J. F. Polak, P. A. Wolf, R. B. D'Agostino, G. H. Tofler, and C. J. O'Donnell Absence of Association Between Polymorphisms in the Hemostatic Factor Pathway Genes and Carotid Intimal Medial Thickness: The Framingham Heart Study Stroke, March 1, 2004; 35 (3): e65 - e67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. McBane II Genetically Determined Procoagulant States and Heparin Use Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2003; 7(4): 427 - 442. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Fontana, A. Dupont, S. Gandrille, C. Bachelot-Loza, J.-L. Reny, M. Aiach, and P. Gaussem Adenosine Diphosphate-Induced Platelet Aggregation Is Associated With P2Y12 Gene Sequence Variations in Healthy Subjects Circulation, August 26, 2003; 108(8): 989 - 995. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Bojesen, K. Juul, P. Schnohr, A. Tybjaerg-Hansen, and B.o. G. Nordestgaard Platelet glycoprotein IIb/IIIa PlA2/PlA2 homozygosity associated with risk of ischemic cardiovascular disease and myocardial infarction in young men: The Copenhagen City Heart Study J. Am. Coll. Cardiol., August 20, 2003; 42(4): 661 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Bojesen, A. Tybjaerg-Hansen, and B. G. Nordestgaard Integrin {beta}3 Leu33Pro Homozygosity and Risk of Cancer J Natl Cancer Inst, August 6, 2003; 95(15): 1150 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. V. Vijayan, Y. Liu, J.-F. Dong, and P. F. Bray Enhanced Activation of Mitogen-activated Protein Kinase and Myosin Light Chain Kinase by the Pro33 Polymorphism of Integrin beta 3 J. Biol. Chem., January 31, 2003; 278(6): 3860 - 3867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sajid, K. V. Vijayan, S. Souza, and P. F. Bray PlA Polymorphism of Integrin {beta}3 Differentially Modulates Cellular Migration on Extracellular Matrix Proteins Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 1984 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Pontiggia, R. Lassila, S. Pederiva, H.-R. Schmid, M. Burger, and J. H. Beer Increased Platelet-Collagen Interaction Associated With Double Homozygosity for Receptor Polymorphisms of Platelet GPIa and GPIIIa Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2093 - 2098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Braunstein, D. W. Kershner, P. Bray, G. Gerstenblith, S. P. Schulman, W. S. Post, and R. S. Blumenthal Interaction of Hemostatic Genetics With Hormone Therapy : New Insights To Explain Arterial Thrombosis in Postmenopausal Women Chest, March 1, 2002; 121(3): 906 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Herrington and K. P. Klein Genome and Hormones: Gender Differences in Physiology: Invited Review: Pharmacogenetics of estrogen replacement therapy J Appl Physiol, December 1, 2001; 91(6): 2776 - 2784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Undas, K. Brummel, J. Musial, K. G. Mann, and A. Szczeklik PlA2 Polymorphism of {beta}3 Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury Circulation, November 27, 2001; 104(22): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Barakat, S. Kennon, G. A. Hitman, E. Aganna, C. P. Price, P. G. Mills, K. Ranjadayalan, B. North, H. Clarke, and A. D. Timmis Interaction between smoking and the glycoprotein IIIa P1A2 polymorphism in Non-ST-elevation acute coronary syndromes J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1639 - 1643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Kandzari and P. J. Goldschmidt-Clermont Platelet polymorphisms and ischemic heart disease: moving beyond traditional risk factors J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1028 - 1032. [Full Text] [PDF]
|
|
|
|
|
|
D. Feng, K. Lindpaintner, M. G. Larson, C. J. O'Donnell, I. Lipinska, P. A. Sutherland, M. Mittleman, J. E. Muller, R. B. D'Agostino, D. Levy, et al. Platelet Glycoprotein IIIa PlA Polymorphism, Fibrinogen, and Platelet Aggregability: The Framingham Heart Study Circulation, July 10, 2001; 104(2): 140 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Bennett, F. Catella-Lawson, A. R. Rut, G. Vilaire, W. Qi, S. C. Kapoor, S. Murphy, and G. A. FitzGerald Effect of the PlA2 alloantigen on the function of {beta}3-integrins in platelets Blood, May 15, 2001; 97(10): 3093 - 3099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Williams and P. F. Bray Genetics of Arterial Prothrombotic Risk States Experimental Biology and Medicine, May 1, 2001; 226(5): 409 - 419. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. Kastrati and A. Schomig Good medicines for bad genes Eur. Heart J., April 1, 2001; 22(7): 523 - 525. [PDF]
|
|
|
|
|
|
D.H Walter, V Schachinger, M Elsner, S Mach, S Dimmeler, W Auch-Schwelk, and A.M Zeiher Statin therapy is associated with reduced restenosis rates after coronary stent implantation in carriers of the PlA2allele of the platelet glycoprotein IIIa gene Eur. Heart J., April 1, 2001; 22(7): 587 - 595. [Abstract] [PDF]
|
|
|
|
|
|
A. Szczeklik, M. Sanak, A. Undas, P. F. Bray, P. Goldschmidt-Clermont, M. I. Furman, A. D. Michelson, M. R. Barnard, M. A. Mascelli, C. Hendrix, et al. Platelet Glycoprotein IIIa PlA Polymorphism and Effects of Aspirin on Thrombin Generation Response Circulation, February 13, 2001; 103 (6): e33 - e34. [Full Text] [PDF]
|
|
|
|
|
|
N. Aleksic, H. Juneja, A. R. Folsom, C. Ahn, E. Boerwinkle, L. E. Chambless, and K. K. Wu Platelet PlA2 Allele and Incidence of Coronary Heart Disease : Results From the Atherosclerosis Risk In Communities (ARIC) Study Circulation, October 17, 2000; 102(16): 1901 - 1905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mikkelsson, M. Perola, P. Laippala, A. Penttila, and P. J. Karhunen Glycoprotein IIIa PlA1/A2 polymorphism and sudden cardiac death J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1317 - 1323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kastrati, W. Koch, M. Gawaz, J. Mehilli, C. Bottiger, K. Schomig, N. von Beckerath, and A. Schomig PlA polymorphism of glycoprotein IIIa and risk of adverse events after coronary stent placement J. Am. Coll. Cardiol., July 1, 2000; 36(1): 84 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Goldschmidt-Clermont, G. E. Cooke, G. M. Eaton, and P. F. Binkley PlA2, a variant of GPIIIa implicated in coronary thromboembolic complications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 90 - 93. [Full Text] [PDF]
|
|
|
|
|
|
A. D. Michelson, M. I. Furman, P. Goldschmidt-Clermont, M. A. Mascelli, C. Hendrix, L. Coleman, J. Hamlington, M. R. Barnard, T. Kickler, D. J. Christie, et al. Platelet GP IIIa PlA Polymorphisms Display Different Sensitivities to Agonists Circulation, March 7, 2000; 101(9): 1013 - 1018. [Abstract] [Full Text] [PDF]
|
|