Correspondence
Platelet Glycoprotein IIIa Pl A Polymorphism and Myocardial Infarction
N Engl J Med 1996; 335:1071-1074October 3, 1996
- Article
To the Editor:
Weiss et al. (April 25 issue)1 report an association between the Pl A2 allele and the risk of myocardial infarction or unstable angina. Because spurious results are common in studies of allelic associations, additional studies with different sets of data are recommended.2,3 We studied the role of this polymorphism in 180 patients with angiographically documented coronary artery disease, including a subgroup of 104 patients with myocardial infarction, and 164 asymptomatic persons who had no history of coronary artery disease and normal physical examinations, electrocardiograms, and echocardiograms. Our results are shown in Table 1Table 1
Glycoprotein IIIa Genotypes and the Frequency of Alleles at the Pl A Locus..We found no association between Pl A1/Pl A2 genotypes and the risk of myocardial infarction or coronary artery disease in either the entire cohort or those under 60 years of age. Our results refute the findings of Weiss et al.1 The differences may reflect the selection of the case patients and controls, the definition of the phenotype in the case patients, and the differences in the size of the sample. The size of the sample in allelic-association studies is a notorious cause of spurious results.2 One cannot ensure the genetic homogeneity of cases and controls according to the Hardy–Weinberg equilibrium or determine the effect of the gene dose. Because of the small sample, it is difficult to explain the greater frequency of heterozygosity among the case patients less than 60 years old than among those more than 60 years old (45 percent [19 of 42] vs. 14 percent [4 of 29]), whereas with regard to homozygosity for the Pl A2 allele the reverse is the case (5 percent vs. 10 percent). It is also unconventional to give a value for the prevalence of an allele regardless of homozygosity or heterozygosity (the prevalence of the Pl A2 allele was reported as 19.1 percent in the controls and 39.4 percent in the case patients). The frequency of the Pl A2 allele should have been reported as 0.1 in the controls and 0.23 in the case patients.
Furthermore, the pooling of patients with myocardial infarction and unstable angina is a potential weakness of the study. Although both are thrombotic events, the clinical diagnosis of unstable angina correlates poorly with the presence of a thrombus, a hypothesis behind this association. Moreover, the reported polymorphism has no known influence on the function of the glycoprotein IIb/IIIa receptor. The Pl A1 /Pl A2 polymorphism could be in linkage disequilibrium with one of the many other polymorphisms in the glycoprotein IIIa gene that are even closer to the known site of ligand binding and more likely to influence its function. Some of these polymorphisms will be associated with myocardial infarction by chance alone. In the absence of functional importance, such associations are more likely to be spurious.
3 ReferencesA.J. Marian, M.D.
Ramon Brugada, M.D.
Neal S. Kleiman, M.D.
Baylor College of Medicine, Houston, TX 770301
Weiss EJ ,Bray PF ,Tayback M , et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996;334:1090-1094
Full Text | Web of Science | Medline2
Lander ES ,Schork NJ . Genetic dissection of complex traits. Science 1994;265:2037-2048[Erratum, Science 1994;266:353.]
CrossRef | Web of Science | Medline3
Lander E ,Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995;11:241-247
CrossRef | Web of Science | Medline
To the Editor:
Weiss et al. describe an association between the Pl A2 polymorphism of platelet glycoprotein IIIa and coronary thrombosis. We have studied the frequency of this polymorphism in 101 white patients under the age of 60 who have a history of myocardial infarction as defined according to the criteria of the World Health Organization1 and 114 white control subjects matched for the sex and age of the patients at the time of their first myocardial infarction. The characteristics of these subjects are shown in Table 1Table 1
Characteristics of the Study Subjects. (next page, top).There was a trend toward a higher incidence of the Pl A2 allele in the patients than in the controls, although this difference was not statistically significant. Differences in Pl A genotypes were not associated with differences with regard to any of the other variables shown. When all the variables were entered into a logistic-regression model, however, the odds ratio for myocardial infarction among persons positive for Pl A2 as compared with persons homozygous for Pl A1 was 1.87 (95 percent confidence interval, 1.19 to 2.93; P = 0.006). The corresponding odds ratios for other factors significantly associated with myocardial infarction were as follows: 1.16 (95 percent confidence interval, 1.05 to 1.28) for an increase of 1 in the body-mass index, 2.04 (1.38 to 3.01) for an increase of 1 mmol per liter in the cholesterol level, 2.39 (1.46 to 3.93) for an increase of 10 years in age, and 3.42 (1.75 to 5.50) for smoking as compared with nonsmoking status.
There are a number of differences between the population studied by Weiss et al. and the one we studied, among them the number of subjects, which was larger in our study. Our patients were selected from among patients recruited at an angiography clinic; therefore, they are not representative of patients with acute myocardial infarction. The incidence of diabetes was considerably lower among our subjects than among the subjects studied by Weiss et al., approximately one third of whom were diabetic. Because diabetics were relatively underrepresented in our population, the stronger independent association of Pl A2 with coronary thrombosis in their patients may suggest that the association is stronger in subjects with diabetes or that Pl A2 is associated with poor survival after myocardial infarction.
1 ReferencesAngela M. Carter, B.Sc.
Nicholas Ossei-Gerning, M.R.C.P.
Peter J. Grant, F.R.C.P.
Leeds General Infirmary, Leeds LS1 3EX, United Kingdom1
Report of the Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature: nomenclature and criteria for diagnosis of ischemic heart disease
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Coronary artery disease is a polygenic disorder, and inherited traits must interact with environmental elements to drive the disease process. We have observed an association between the events of coronary artery disease and the polymorphic allele Pl A2 of the gene encoding glycoprotein IIIa, a component of the glycoprotein IIb/IIIa receptor on the platelet surface. The pivotal part played by platelets and their glycoprotein IIb/IIIa receptors in coronary artery disease made this association particularly interesting.
Marian et al. studied the Pl A genotype of patients with coronary artery disease and controls but were unable to corroborate our findings. Unfortunately, we do not know whether their two groups were matched for other established risk factors, and therefore we have no way of assessing the validity of their findings. Nevertheless, we would like to respond to specific points they raise. First, they indicate that the Pl A2 polymorphism has no known influence on the function of glycoprotein IIb/IIIa. Before our study, however, this polymorphism was not investigated with regard to its thrombogenicity. Furthermore, most anti-Pl A1 antibodies block the binding of fibrinogen to glycoprotein IIb/IIIa. These antibodies inhibit the aggregation of platelets that have the Pl A1/Pl A1 genotype but only retard that of those with the Pl A1/Pl A2 genotype,1 suggesting that the substitution of proline for leucine may have structural effects on glycoprotein IIIa that are relevant to the thrombogenicity of platelets.
Second, concerning the pooling of patients with myocardial infarction and unstable angina in our study, in Table 1Table 1
Patients with Myocardial Infarction or Unstable Angina Studied by Weiss et Al., According to Pl A Status and Type of Cardiac Event. we provide a breakdown of our patients according to Pl A status and type of event. Patients with unstable angina represent less than 10 percent of the total. Third, we have studied five other common polymorphisms of platelets, including Pen on glycoprotein IIIa and Bak on glycoprotein IIb, in a blinded fashion and have found that only Pl A2 was associated with coronary artery disease. Therefore, we see no reason why the association with Pl A2 should be selectively spurious.Carter et al. report data supporting the association between Pl A2 and coronary artery disease, although the association is weaker than in our report. It is noteworthy that in our study, unlike those described by all these writers, the patients were admitted to the coronary care unit for acute coronary events. At Johns Hopkins, such patients usually have complicated conditions and are referred for problems such as postinfarction angina, and perhaps the risk associated with Pl A2 is strongest in this population. We agree with Carter et al. that the differences in demographic characteristics (the prevalence of diabetes mellitus, smoking status, and the like) between their subjects and ours could influence the effect on coronary artery disease of a factor such as Pl A2.
Little is known about the inherited risk classified as “positive family history.” Characterizing inherited risk factors will not be a trivial matter, and resolving conflicts among the findings of different investigators will ultimately define the groups of patients to which these risk factors apply.2 We remain convinced that the Pl A2 phenotype is a risk factor for coronary artery disease and that functional consequences of this alteration will gradually be elucidated.
2 ReferencesPascal J. Goldschmidt-Clermont, M.D.
Paul F. Bray, M.D.
Johns Hopkins University, Baltimore, MD 212051
Kunicki TJ. Biochemistry of platelet-associated isoantigens and alloantigens. In: Kunicki TJ, George JN, eds. Platelet immunobiology: molecular and clinical aspects. Philadelphia: Lippincott, 1989:99-120.
2
Singer DRJ ,Missouris CG ,Jeffery S . Angiotensin-converting enzyme gene polymorphism: what to do about all the confusion? Circulation 1996;94:236-239
Web of Science | Medline
- Citing Articles (28)
Citing Articles
1
Anna M. Kucharska-Newton, Keri L. Monda, Stephen Campbell, Patrick T. Bradshaw, Lynne E. Wagenknecht, Eric Boerwinkle, Bruce A. Wasserman, Gerardo Heiss. (2011) Association of the platelet GPIIb/IIIa polymorphism with atherosclerotic plaque morphology. Atherosclerosis 216:1, 151-156
CrossRef2
Teresa Cymbron, Mafalda Raposo, Nadiya Kazachkova, Conceição Bettencourt, Francisca Silva, Cristina Santos, Yahya Dahmani, Paula Lourenço, Rita Ferin, Maria Leonor Pavão, Manuela Lima. (2011) Cross-sectional study of risk factors for atherosclerosis in the Azorean population. Annals of Human Biology 38:3, 354-359
CrossRef3
A. Travlou, A. Gialeraki, E. Merkouri, M. Politou, A. Sfyridaki, M. Neerman-Arbez. (2010) Coexisting dysfibrinogenemia (γArg275His) and FV Leiden associated with thrombosis (Fibrinogen Crete). Thrombosis Research 126:2, e162-e164
CrossRef4
(2009) HPA-1 allelic frequencies in the Greek population. Transfusion Medicine 19:1, 53-54
CrossRef5
Argyri Gialeraki, Marianna Politou, Loukianos Rallidis, Efrosyni Merkouri, Christos Markatos, Dimitrios Kremastinos, Anthi Travlou. (2008) Prevalence of Prothrombotic Polymorphisms in Greece. Genetic Testing 12:4, 541-547
CrossRef6
A. S. Sabbagh, A. T. Taher, G. S. Zaatari, R. A. R. Mahfouz. (2007) Gene frequencies of the HPA-1 platelet antigen alleles in the Lebanese population. Transfusion Medicine 17:6, 473-478
CrossRef7
Timothy Goodman, Pankaj Sharma, Albert Ferro. (2007) The genetics of aspirin resistance. International Journal of Clinical Practice 61:5, 826-834
CrossRef8
Massimo Franchini, Dino Veneri, Gian Luca Salvagno, Franco Manzato, Giuseppe Lippi. (2006) Inherited Thrombophilia. Critical Reviews in Clinical Laboratory Sciences 43:3, 249-290
CrossRef9
Hyun-Young Park. (2005) The glycoprotein IIIa gene polymorphism and the risk of myocardial infarction. Future Cardiology 1:2, 207-214
CrossRef10
Philippe H. Jais. (2005) How frequent is altered gene expression among susceptibility genes to human complex disorders?. Genetics in Medicine 7:2, 83-96
CrossRef11
TM Morgan, CS Coffey, HM Krumholz. (2003) Overestimation of genetic risks owing to small sample sizes in cardiovascular studies. Clinical Genetics 64:1, 7-17
CrossRef12
Deborah Burr, Hani Doss, Glen E. Cooke, Pascal J. Goldschmidt-Clermont. (2003) A meta-analysis of studies on the association of the platelet PlA polymorphism of glycoprotein IIIa and risk of coronary heart disease. Statistics in Medicine 22:10, 1741-1760
CrossRef13
Felicity B. Smith, J.Michael Connor, Amanda J. Lee, Alexander Cooke, Gordon D.O. Lowe, Ann Rumley, F.Gerald Fowkes. (2003) Relationship of the platelet glycoprotein PlA and fibrinogen T/G+1689 polymorphisms with peripheral arterial disease and ischaemic heart disease. Thrombosis Research 112:4, 209-216
CrossRef14
Kenneth S. Kornman, Gordon W. Duff. (2001) Candidate Genes as Potential Links Between Periodontal and Cardiovascular Diseases. Annals of Periodontology 6:1, 48-57
CrossRef15
Rendrik F. Franco, Pieter H. Reitsma. (2001) Gene polymorphisms of the haemostatic system and the risk of arterial thrombotic disease. British Journal of Haematology 115:3, 491-506
CrossRef16
B. Schwippert-Houtermans, S. Strapatsakis, P. Roesen, D. Tschoepe. (2001) Evaluation of an antibody-based genotype classification of the platelet fibrinogen receptor (GPIIb/IIIa). Cytometry 46:4, 238-242
CrossRef17
D. J. Meiklejohn, M. A. Vickers, E. R. Morrison, R. Dijkhuisen, I. Moore, S. J. Urbaniak, M. Greaves. (2001) In vivo platelet activation in atherothrombotic stroke is not determined by polymorphisms of human platelet glycoprotein IIIa or Ib. British Journal of Haematology 112:3, 621-631
CrossRef18
Jussi Mikkelsson, Markus Perola, Pekka Laippala, Antti Penttilä, Pekka J. Karhunen. (2000) Glycoprotein IIIa PlA1/A2 polymorphism and sudden cardiac death. Journal of the American College of Cardiology 36:4, 1317-1323
CrossRef19
Bassam A Nassar, Jeremy Dunn, Lawrence M Title, Blair J O’Neill, Susan A Kirkland, Ekram Zayed, Iqbal R Bata, Richard C Cantrill, Jenny Johnstone, Gale I Dempsey, Meng-Hee Tan, W.Carl Breckenridge, David E Johnstone. (1999) Relation of genetic polymorphisms of apolipoprotein E, angiotensin converting enzyme, apolipoprotein B-100, and glycoprotein IIIa and early-onset coronary heart disease. Clinical Biochemistry 32:4, 275-282
CrossRef20
Ana Cenarro, Elena Casao, Fernando Civeira, Henrik K. Jensen, Ole Færgeman, Miguel Pocovı́. (1999) PlA1/A2 polymorphism of platelet glycoprotein IIIa and risk of acute coronary syndromes in heterozygous familial hypercholesterolemia. Atherosclerosis 143:1, 99-104
CrossRef21
(1999) Point - Counterpoint: The wide use of IIb/IIIa inhibitors in interventional cardiology - is it justified?. Acute Cardiac Care 2:1, 61-70
CrossRef22
Sherri A. Zimmerman, Russell E. Ware. (1998) Inherited DNA mutations contributing to thrombotic complications in patients with Sickle cell disease. American Journal of Hematology 59:4, 267-272
CrossRef23
Mariano Sentí, Clara Aubó, Mireia Bosch, Marco Pavesi, Araceli Pena, Rafel Masiá, Jaume Marrugat. (1998) Platelet glycoprotein IIb/IIIa genetic polymorphism is associated with plasma fibrinogen levels in myocardial infarction patients. Clinical Biochemistry 31:8, 647-651
CrossRef24
Jorge Joven, José M Simó, Elisabet Vilella, Jordi Camps, Luis Masana, Gabriel de Febrer, Mercè Camprubı́, Cristobal Richart, Alfredo Bardaji, Elena Casao, Miguel Pocovi, Fernando Civeira. (1998) Lipoprotein(a) and the significance of the association between platelet glycoprotein IIIa polymorphisms and the risk of premature myocardial infarction. Atherosclerosis 140:1, 155-159
CrossRef25
Scaglione, Bergerone, Gaschino, Imazio, Maccagnani, Gambino, Cassader, Di Leo, Macchia, Brusca, Pagano, Cavallo-Perin. (1998) Lack of relationship between the PlA1/PlA2 polymorphism of platelet glycoprotein IIIa and premature myocardial infarction. European Journal of Clinical Investigation 28:5, 385-388
CrossRef26
Uttam C Garg, Donna K Arnett, Aaron R Folsom, Michael A Province, Roger R Williams, John H Eckfeldt. (1998) Lack of Association between Platelet Glycoprotein IIb/IIIa Receptor PlA Polymorphism and Coronary Artery Disease or Carotid Intima-Media Thickness. Thrombosis Research 89:2, 85-89
CrossRef27
Alan T Nurden. (1997) Platelet glycoprotein Illa polymorphism ane coronary thrombosis. The Lancet 350:9086, 1189-1191
CrossRef28
Peter J Newman. (1997) Platelet alloantigens: cardiovascular as well as immunological risk factors?. The Lancet 349:9049, 370-371
CrossRef
