Distribution of Tissue Plasminogen Activator Insertion/Deletion Polymorphism in Myocardial Infarction and Control Subjects

Summary

An insertion (I)/deletion (D) polymorphism in the tissue plasminogen activator (TPA) gene locus has recently been reported to be associated with the risk of myocardial infarction (MI) with increased risk in II/ID subjects compared with DD subjects. To investigate this further, we analysed 529 acute MI cases and 525 population-based control subjects recruited in two centers (Leicester and Sheffield, UK). We found no difference between cases and controls in TPA I/D allele frequencies (cases I = 0.574, controls I = 0.582, p = 0.74) or genotype distribution (cases II 33%, ID 48%, DD 19%; controls II 34%, ID 49%, DD 17%, p = 0.88). Compared with the DD genotype, the age, sex and centre adjusted odds ratios for MI for II genotype was 0.95 (95% confidence interval, 0.64 – 1.40, p = 0.85) and that for ID genotype was 0.89 (0.62-1.27, p = 0.56). There was no significant effect modification by smoking status, body mass index or cholesterol level. There was no difference in the reported frequency of positive family history of coronary heart disease or mean age at MI in the different genotype groups. We conclude that in our populations the TPA I/D polymorphism is not a major independent risk factor for myocardial infarction.

• References

• 1 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50.
• 2 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 1988; 2: 349-60.
• 3 Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. JAMA 1996; 276: 811-5.
• 4 Antiplatelet Trialists’ Collaboration.. Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81-106.
• 5 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller CJ. Fibrinolytic activity, clotting factors and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
• 6 Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM study in healthy men. Arterioscle Throm 1994; 14: 54-9.
• 7 Hamsten A, Wiman B, Defaire U, Blombäck M. Increased plasma level of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1157-63.
• 8 Dawson S, Hamsten A, Wiman B, Henney A, Humphries S. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasminogen activator inhibitor-1 activity. Arterioscle Throm 1991; 11: 183-90.
• 9 Green F, Hamsten A, Blombäck M, Humphries S. The role of beta-fibrino gen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden. Thromb Haemostas 1993; 70: 915-20.
• 10 Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
• 11 Munkvad S, Gram J, Jespersen J. A depression of active tissue plasminogen activator in plasma characterises patients with unstable angina who develop myocardial infarction. Eur Heart J 1990; 6: 525-8.
• 12 Gram J, Jespersen J. A selective depression of tissue plasminogen activator (t-PA) activity in euglobulin characterises a risk group among young survivors of acute myocardial infarction. Throm Haemost 1987; 57: 137-9.
• 13 Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW. for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic risk factor and risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-41.
• 14 Jansson H, Nilsson TK, Olofsson BO. Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. Eur Heart J 1991; 12: 157-61.
• 15 Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease: a 7-year follow-up. Circulation 1993; 88: 2030-4.
• 16 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
• 17 van der Bom JG, de Knijff P, Haverkate F, Bots ML, Meijer P, de Jong PTVM, Hofman A, Kluft C, Grobbee DE. Tissue plasminogen activator and risk of myocardial infarction: The Rotterdam study. Circulation 1997; 95: 2623-7.
• 18 de Bono DP. Significance of raised plasma concentrations of tissue-type plasminogen activator and plasminogen activator inhibitor in patients at risk from ischaemic heart disease. Br Heart J 1994; 71: 504-7.
• 19 Ridker PM, Douglas EV. Hemostatic factors and risk of myocardial infarction. N Engl J Med 1995; 333: 389-90.
• 20 Ludwig M, Wohn KD, Schleuning WD, Olek K. Allelic dimorphism in the human tissue-type plasminogen activator (t-PA) gene as a result of an Alu insertion/deletion event. Hum Genet 1992; 88: 388-92.
• 21 WHO (Report of the joint International Society and Federation of Cardiology/World Health Organisation Task Force on standardization of clinical nomenclature).. Nomenclature and criteria for diagnosis of ischaemic heart disease. Circulation 1979; 59: 607-9.
• 22 Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: A laboratory manual . Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1989
• 23 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: 1041-6.
• 24 Hegle RA, Huang L-S, Herbert PN, Blum CB, Buring JE, Hennekens CH, Breslow JL. Apolipoprotein B-gene DNA polymorphisms associated with myocardial infarction. N Engl J Med 1986; 315: 1509-15.
• 25 van Bockxmeer FM, Marmotte CD. Apolipoprotein E4 homozygosity in young men with coronary heart disease. Lancet 1992; 340: 879-80.
• 26 Cambien F, Poirier O, Lecerf L, Evans A, Cambou J-P, Arveiler D, Luc G, Bard J-M, Bara L, Ricard S, Tiret L, Amouyel P, Alhenc-Gelas F, Soubrier F. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359: 641-3.
• 27 Wang XL, Sim AS, Badenhop RF, McCredie RM, Wilcken DEL. A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nat Med 1996; 2: 41-5.
• 28 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.
• 29 Samani NJ, Thompson JR, O’Toole L, Channer K, Woods KL. A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation 1996; 94: 708-12.
• 30 Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpaintner K. PlA1/A2 polymorphism of the platelet glycoprotein IIIa and risks of myocardial infarction, stroke and venous thrombosis. Lancet 1997; 349: 385-8.
• 31 Degen SJF, Rajput B, Reich E. The human tissue-type plasminogen activator gene. J Biol Chem 1986; 261: 6972-85.
• 32 Tiret L, Kee F, Poirier O, Nicaud V, Lecerf L, Evans A, Cambou J-P, Arveiler D, Luc G, Amouyel P, Cambien F. Deletion polymorphism in the angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet 1993; 341: 991-2.
• 33 Badenhop RF, Wang XL, Wilcken DEL. Angiotensin-converting enzyme genotype in children and coronary events in their grandparents. Circulation 1995; 91: 1655-8.
• 34 Kee F, Tiret L, Robo JY, Nicaud V, McCrum E, Evans A, Cambien F. Reliability of a reported family hsitory of myocardial infarction. BMJ 1993; 307: 1528-30.