The 4G/5G Genetic Polymorphism in the Promoter of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene Is Associated with Differences in Plasma PAI-1 Activity but not with Risk of Myocardial Infarction in the ECTIM Study

S Ye; F R Green; P Y Scarabin; V Nicaud; L Bara; S J Dawson; S E Humphries; A Evans; G Luc; J P Cambou; D Arveiler; A M Henney; F Cambien

doi:10.1055/s-0038-1649833

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1995; 74(03): 837-841
DOI: 10.1055/s-0038-1649833

Original Article

Clinical Studies

Schattauer GmbH Stuttgart

The 4G/5G Genetic Polymorphism in the Promoter of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene Is Associated with Differences in Plasma PAI-1 Activity but not with Risk of Myocardial Infarction in the ECTIM Study

Authors

S Ye

¹The Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, London UK
F R Green

¹The Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, London UK
P Y Scarabin

²The INSERM U258, Hôpital Broussais, Paris, France
V Nicaud

²The INSERM U258, Hôpital Broussais, Paris, France
L Bara

³The Laboratolre de Thrombose Experimentale, Universite Paris VI, France
S J Dawson

¹The Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, London UK
S E Humphries

¹The Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, London UK
A Evans

⁴The MONICA project, Belfast, UK
G Luc

⁵The MONICA project, Lille, France
J P Cambou

⁶The MONICA project, Toulouse, France
D Arveiler

⁷The MONICA project, Strasbourg, France
A M Henney

¹The Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, London UK
F Cambien

⁸The SC No7, Banque dADN pour la Recherche Cardiovasculaire, Paris, France

Abstract

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Summary

We have investigated the interrelationships of plasma PAI-1 activity, the PAI-1 4G/5G polymorphism and risk of myocardial infarction (MI) in the ECTIM study, a case-control study of MI based in Belfast, Lille, Strasbourg and Toulouse. Mean PAI-1 levels in cases were similar across all centres but in controls, levels in the French centres were significantly higher. Only in Belfast were PAI-1 levels higher in cases (11.7AU/ml) than controls (10.5AU/ml). The PAI-1 4G allele frequency was similar in cases and controls (0.55 and 0.54). In all groups, 4G homozygotes had the highest mean plasma PAI-1 level (4G4G vs 5G5G; cases overall: 14.2 vs 12.1 AU/ml; controls overall: 15.0 vs 12.6AU/ml), with the heterozygotes generally intermediate. The data from Belfast are consistent with the literature implicating PAI-1 level as an MI risk factor. In ECTIM, the PAI-1 4G/5G polymorphism is not a genetic risk factor for MI but is associated with PAI-1 activity. Thus homozygosity for the 4G allele may predispose to elevated PAI-1 and impaired fibrinolysis, perhaps requiring interaction with other genetic or environmental factors to influence MI risk.

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References

References
1 Aznar J, Estelles A, Tormo G, Sapena P, Tormo V, Blanch S, Espana F. Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J 1988; 59: 535-541
2 Almer L, Ohlin H. Elevated levels of the rapid inhibitor of plasminogen activator (t-PA) in acute myocardial infarction. Thromb Res 1987; 47: 335-339
3 Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator inhibitor in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563
4 Hamsten A, Blomback M, Wiman B, Svensson J, Szamosi A, de Faire U, Mettinger L. Haemostatic function in myocardial infarction. Br Heart J 1986; 55: 58-66
5 Johnson O, Mellbring G, Nilsson T. Defective fibrinolysis in survivors of myocardial infarction. Int J Cardiol 1984; 6: 380-382
6 Paramo JA, Colucci M, Collen D, van de Werf F. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 573-574
7 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9
8 Han P, Koay ES C, Tsakok M, Wong LY, Pradhan M. Altered fibrinolysis in DVT: influence of site of sampling. Thromb Haemost 1988; 60: 50-53
9 Julian-Vague I, Valadier J, Alessi MC, Aillaud MF, Ansaldi J, Philip- Joel C, Holvoet P, Serradimigni A, Collen D. Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemost 1987; 57: 67-72
10 Fisher M, Francis R. Altered coagulation in cerebral ischemia. Arch Neurol 1999; 47: 1075-1079
11 Castellino FJ. Biochemistry of human plasminogen. Semin Thromb Haemostas 1984; 10: 18-23
12 Mantgan RR, Handt S, Kirkpatrick CJ, Lewis JC. Role of platelet-released PAN in regulation of fibrinolysis. Thromb Haemost 1991; 65: 718
13 Kruithof EK O, Tran-Thang C, Ransijn A, Bachmann F. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood 1984; 64: 907-913
14 Lindahl TL, Ohlsson PI, Wiman B. The mechanism of the reaction between human plasminogen activator inhibitor I and tissue plasminogen activator. Biochem J 1990; 265: 109-113
15 Ailland MF, Juhan-Vague I, Alessi MC, Marecal M, Vinson ML, Arnaud C, Vague PH, Collen D. Increased PA-inhibitor levels in the postoperative period - no cause-effect relation with increased cortisol. Thromb Haemost 1985; 54: 466-468
16 Kluft C, Verheijen JH, Jie AF H, Rijken DC, Preston FE, Sue-Ling HM, Jespersen J, Aasen AD. The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest 1985; 45: 605-610
17 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 60: 381-387
18 Juhan-Vague I, Vague P, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationship between plasma insulin, triglyceride, body mass index, and plasminogen activator inhibitor. J Diabete Metab 1987; 13: 331-336
19 Mehta J, Mehta P, Lawson D, Saldeen T. Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations. J Am Coll Cardiol 1987; 9: 263-268
20 Vague P, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, Collen D. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism 1986; 2: 250-253
21 Vague P, Juhan-Vague I, Alessi MC, Badier C, Valadier J. Metformin decrease the high plasminogen activator capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemost 1987; 57: 326-328
22 Mitrio V, Perricci A, Lomuscio S, Scaraggi FA, De Pergola G, Cignarelli M, Ferri G, Giorgino R, Schiraldi O. Relationship between androgenic activity, insulin and plasminogen activator inhibitor type 1 (PAI-1) in premenopausal women with abdominal obesity. Thromb Res 1991; Suppl 13: 23
23 Takada Y, Takada A. Plasma levels of t-PA free PAI-1 and a complex of t-PA with PAI-1 in human males and females at various ages. Thromb Res 1989; 55: 601-609
24 Scarabin PY, Bonithon-Kopp C, Bara L, Guize L, Samama M. Relationship between plasminogen activator inhibitor activity and menopausal status. Fibrinolysis 1990; 4: 233-236
25 Philips M, Juul AG, Thorsen S. Human endothelial cells produce a plasminogen activator inhibitor complex. Biochem Biophys Acta 1984; 802: 099-110
26 Simpson AJ, Booth NA, Moore NR, Bennett B. Distribution of PAI-1 in tissue. J Clin Pathol 1991; 44: 139-143
27 Kruithof EK O, Trans-Thang C, Bachman F. Studies on the release of PAI-1 from human platelets. Thromb Haemost 1986; 55: 201-205
28 Booth NA, Simpson AJ, Croll A, Bennet B, MacGregor IR. PAI-1 in plasma and platelets. Brit J Haematol 1988; 70: 327-333
29 Klinger KW, Winqvist R, Riccio A, Anderasen PA, Sartorio R, Nielsen LS, Stuart N, Stanislovitis P, Watkins P, Douglas R, Grzeschik KH, Alitalo K, Blasi F, Dano K. Plasminogen activator inhibitor type I gene is located at region q2l.3-q22 of chromosome 7 and genetically linked with cystic fibrosis. Proc Natl Acad Sci USA 1987; 84: 8548-8552
30 Follo M, Ginsburg D. Structure and expression of the human gene encoding plasminogen activator inhibitor, PAI-1. Gene 1989; 84: 447-453
31 Bosma PJ, van den Berg LA, Kooistra T. Human PAI-I gene. J Biol Chem 1988; 263: 9129-9141
32 Heaton JH, Nebes VL, O’Dell LG, Morris Jr SM, Gelehrter TD. Glucocorticoid and cyclic nucleotide regulation of plasminogen activator and plasminogen activator inhibitor gene expression in primary cultures of rat hepatocytes. Mol Endocrinol 1989; 3: 185-192
33 Heaton JH, Gelehrter TD. Glucocorticoid induction of plasminogen activator and plasminogen activator inhibitor messenger RNA in rat hepatoma cells. Mol Endocrinol 1989; 3: 349-355
34 de Boer JP, Abbink JJ, Brouwer MC, Meijer C, Roem S, Voorn GP, Lambers JW J, van Mourik JA, Hack CE. PAI-1 synthesis in the human hepatoma cell line hep G2 is increased by cytokines - evidence that the liver contributes to acute phase behaviour of PAI-I. Thromb Haemost 1991; 65: 181-185
35 Dichek D, Quertermous T. Thrombin regulation of mRNA levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in cultured human umbilical vein endothelial cells. Blood 1989; 74: 222-228
36 Gelehrter TD, Sznycer-Laszuk R. Thrombin induction of plasminogen activator inhibitor in cultured human endothelial cells. J Clin Invest 1986; 78: 1673-1680
37 Ginsburg D. Regulation of PAI-1 gene expression. Thromb Haemost 1991; 65: 740
38 Riccio A, Lund LR, Sartorio R, Lania A, Anderasen PA, Dano K, Blasi F. The regulatory region of the human plasminogen activator inhibitor type-1 (PAI-1) gene. Nucleic Acids Res 1988; 16: 2805-2824
39 Dawson S, Hamsten A, Wiman B, Henney A, Humphries SE. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasminogen activator inhibitors-1 activity. Arterioscler Thromb 1991; 11: 183-190
40 Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to IL-1 in Hep G2 cells. J Biol Chem 1993; 268 (15) 10739-10745
41 Parra HJ, Arveiler D, Evans AE, Cambou JP, Amouyel P, Bingham A, McMaster D, Schaffer P, Douste-Blazy Ph, Luc G, Richard JL, Ducimctièrc P, Fruchart JC, Cambien F. A case-control study of lipoprotein particles in two populations at contrasting risk for coronary heart disease the ECTIM study. Arterioscler Thromb 1992; 12: 701-707
42 Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, Luc G, Bard M, Bara L, Richard 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: 641-644
43 Eriksson E, Ranby M, Gyzander E, Risberg B. Determination of plasminogen activator inhibitor in plasma using t-PA and a chromogenic single-point poly-d-lysine stimulated assay. Thromb Res 1988; 50: 091-101
44 Eguchi Y, Keeton M, Sawdey M, Loskutoff D. Endotoxin induces the expression of PAI-1 protein and mRNA by endothelial cells in mouse tissue in vivo. Thromb Haemost 1991; 65: 652
45 Eriksson E, Tengbom L, Risberg B. The effect of various anticoagulant/antiplatelet mixtures on determination of plasminogen activator, platelet proteins and heamostasis parameters. Thromb Haemost 1989; 61: 511-516
46 Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries SE, Yudkin JS. Determinants of plasminogen activator inhibitor 1 activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor 1 gene. Diabetes 1995; 44: 37-42
47 Huber K, Rosc A, Resch I, Schuster E, Gloger DH, Kaindl F, Binder BR. Circadian fluctuations of plasminogen activator inhibitor and tissue plasminogen activator levels in plasma of patients with unstable coronary artery disease and acute myocardial infarction. Thromb Haemost 1988; 60: 372