Tissue-type Plasminogen Activator –7,351C/T Enhancer Polymorphism Is Associated with a First Myocardial Infarction

Summary

We recently identified a polymorphic Sp1 binding site in an enhancer at the tissue-type plasminogen activator (tPA) locus (tPA –7,351C/T), which was associated with vascular tPA release. Subjects homozygous for the –7,351C allele had twice the tPA release rate compared to subjects carrying the –7,351T allele. In this study we tested the hypothesis that the tPA –7,351C/T polymorphism is associated with myocardial infarction (MI). In a population-based prospective nested case-control study within northern Sweden, genotypes were determined among 61 MI cases and 120 controls. In a multivariate model, the tPA –7,351C/T polymorphism (OR 2.68 for T allele carriers; 95% CI 1.31– 5.50), tPA antigen (OR 1.16; 95% CI 1.07–1.25) and apo A-I (OR, 0.997; 95% CI 0.995–0.999) were independently associated with a first MI. These findings suggest that genetic markers of local tPA release and circulating steady-state tPA levels carry independent prognostic information.

Keywords

Myocardial infarction - tissue-type plasminogen activator - enhancer - polymorphism

^* Both authors contributed equally to this work

• References

• 1 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657-71.
• 2 Rentrop KP, Feit F, Blanke H. et al. Serial angiographic assessment of coronary artery obstruction and collateral flow in acute myocardial infarction. Circulation 1987; 80: 1166-75.
• 3 Emeis JJ. Regulation of the acute release of tissue-type plasminogen activator from endothelium by coagulation products. Ann NY Acad Sci 1992; 667: 249-58.
• 4 Carmeliet P, Collen D. Gene targeting and gene transfer studies of the biological role of the plasminogen/plasmin system. Thromb Haemost 1995; 74: 429-36.
• 5 Matsuno H, Kozawa O, Niwa M. et al. Differential role of components of the fibrinolytic system in the formation and removal of thrombus induced by endothelial injury. Thromb Haemost 1999; 81: 601-4.
• 6 Ridker PM, Vaughan DE, Stampfer MJ. et al. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
• 7 Thögersen AM, Jansson JH, Boman K. et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-7.
• 8 Jansson JH, 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.
• 9 Jern C, Selin L, Jern S. In vivo release of tissue-type plasminogen activator across the human forearm during mental stress. Thromb Haemost 1994; 72: 285-91.
• 10 Jern S, Selin L, Bergbrant A. et al. Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm. Thromb Haemost 1994; 72: 588-94.
• 11 Jern C, Ladenvall P, Wall U. et al. Gene polymorphism of tissue-type plasminogen activator (tPA) is associated with forearm vascular release rate of tPA. Arterioscler Thromb Vasc Biol 1999; 19: 454-9.
• 12 Ladenvall P, Wall U, Jern S. et al. Identification of eight novel singlenucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus: Association with vascular t-PA release. Thromb Haemost 2000; 84: 150-5.
• 13 Weinehall L, Johnson O, Jansson JH. et al. Perceived health modifies the effect of biomedical risk factors in the prediction of acute myocardial infarction. An incident case-control study from northern Sweden. J Intern Med 1998; 243: 99-107.
• 14 Livak KJ, Todd JA. Towards fully automated genome-wide polymorphism sceening. Nat Genet 1995; 09: 341-2.
• 15 Merchiers P, Bulens F, de Vriese A. et al. Involvement of Sp1 in basal and retinoic acid transcription of the human tissue-type plasminogen activator gene. FEBS Letters 1999; 456: 149-54.
• 16 Chandler WL, Alessi MC, Aillaud MF. et al. Clearance of tissue plasminogen activator (tPA) and tPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated tPA antigen in patients with high PAI-1 activity levels. Circulation 1997; 96: 761-8.
• 17 Nilsson TK. Analysis of factors affecting tissue plasminogen activator activity and antigen concentration before and after venous occlusion in 123 patients. Clin Chem Enzymol Commun 1989; 01: 335-41.
• 18 Wall U. In vivo studies on local release of tissue-type plasminogen activator from vascular endothelium. Thesis, Göteborg University; 1997
• 19 Jern S, Wall U, Bergbrant A. et al. Endothelium-dependent vasodilation and tissue-type plasminogen activator release in borderline hypertension. Arterioscler Thromb Vasc Biol 1997; 17: 3376-83.
• 20 van der Bom JG, de Knijff P, Haverkate F. et al. Tissue plasminogen activator and risk of myocardial infarction: the Rotterdam study. Circulation 1997; 95: 2623-7.
• 21 Iacoviello L, Di Castelnuovo A, de Knijff P. et al. Alu-repeat polymorphism in the tissue-type plasminogen activator (tPA) gene, tPA levels and risk of familial myocardial infarction (MI). Fibrinolysis 1996; 10 (Suppl. 02) 13-6.
• 22 Ridker PM, Baker MT, Hennekens CH. et al. Alu-repeat polymorphism in the gene coding for tissue-type plasminogen activator (tPA) and risks of myocardial infarction among middle-aged men. Arterioscler Thromb Vasc Biol 1997; 17: 1687-90.
• 23 Steeds R, Adams M, Smith P. et al. Distribution of tissue plasminogen activator insertion/deletion polymorphism in myocardial infarction and control subjects. Thromb Haemost 1998; 79: 980-4.