Plasminogen Activator Inhibitor-1 (PAI-1) Promoter 4G/5G Genotype and Increased PAI-1 Circulating Levels in Postmenopausal Women with Coronary Artery Disease

S. Grancha; A. Estellés; G. Tormo; C. Falco; J. Gilabert; F. España; A. Cano; R. Segui; J. Aznar

doi:10.1055/s-0037-1614516

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 81(04): 516-521
DOI: 10.1055/s-0037-1614516

Rapid Communication

Schattauer GmbH

Plasminogen Activator Inhibitor-1 (PAI-1) Promoter 4G/5G Genotype and Increased PAI-1 Circulating Levels in Postmenopausal Women with Coronary Artery Disease

Influence of Hormone Replacement Therapy

Authors

S. Grancha

¹From the University Hospital La Fe, Valencia, Spain
A. Estellés

¹From the University Hospital La Fe, Valencia, Spain
G. Tormo

²General Hospital, Valencia, Spain
C. Falco

¹From the University Hospital La Fe, Valencia, Spain
J. Gilabert

¹From the University Hospital La Fe, Valencia, Spain
F. España

¹From the University Hospital La Fe, Valencia, Spain
A. Cano

³School of Medicine, University of Valencia, Valencia, Spain
R. Segui

¹From the University Hospital La Fe, Valencia, Spain
J. Aznar

¹From the University Hospital La Fe, Valencia, Spain

Abstract

Summary

Increased circulating levels of type 1 plasminogen activator inhibitor (PAI-1) have been associated with coronary artery disease (CAD). However, genetic and environmental determinants of PAI-1 expression are only partially understood. The levels of PAI-1 have been found to relate to 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene. The 4G allele in this polymorphism has been associated with higher levels of plasma PAI-1 activity, but despite the strong correlation between PAI-1 activity and antigen, no association has been found between PAI-1 antigen levels and the PAI-1 promoter 4G/5G genotype. The aim of the present study was to analyze the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels in post-menopause women with coronary disease in comparison with healthy women in pre and postmenopausal status, and the influence of this genotype on variations in PAI-1 levels after hormone replacement therapy (HRT). No differences between 4G/5G allele distribution in the groups studied were observed. The group of postmenopausal women with CAD showed significantly increased PAI-1 antigen and activity levels in comparison with the control groups, and the levels of PAI-1 correlated with the 4G/5G genotype. A multivariate analysis revealed that in the CAD group there was a high correlation between 4G allele dosage and PAI-1 antigen levels, which were also influenced by the triglyceride levels but not by estrogen or glucose levels. After hormone replacement therapy the decrease in PAI-1 levels was correlated with the 4G allele dosage. We conclude that in the group of postmenopausal women with CAD the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels is more evident than in the control groups, and that the decrease in PAI-1 levels after HRT in CAD women correlates with the 4G allele dosage.

Full Text

References

References
1 Loskutoff DJ. Regulation of PAI-1 gene expression. Fibrinolysis 1991; 5: 197-206.
2 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-7.
3 van Meijer M, Pannekoek H. Structure of plasminogen activator inhibitor-1 (PAI-1) and its function in fibrinolysis: an update. Fibrinolysis 1995; 9: 263-76.
4 Chakrabarti R, Hocking ED, Fearnley GR, Mann RD, Attwell TN, Jackson D. Fibrinolytic activity and coronary artery disease. Lancet 1968; 1: 987-90.
5 Estellés A, Tormo G, Aznar J, España F, Tormo V. Reduced fibrinolytic activity in coronary heart disease in basal conditions and after exercise. Thromb Res 1985; 40: 373-83.
6 Páramo JA, Colucci M, Collen D. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Brit Med J 1985; 291: 573-4.
7 Hamsten A, Wiman B, De Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
8 Aznar J, Estellés A, Tormo G, Sapena P, Tormo V, Blanch S, España F. Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Brit Heart J 1988; 59: 535-41.
9 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A Landou, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
10 ECAT angina pectoris study group. ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993; 14: 8-17.
11 Schneiderman J, Sawdey MS, Keeton MR, Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci USA 1992; 89: 6998-7002.
12 Lupu F, Bergonzelli GE, Heim DA, Cousin E, Genton CY, Bachmann F, Kruithof EKO. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 1993; 13: 1090-100.
13 Robbie LA, Booth NA, Brown PAJ, Bennett B. Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler Thromb Vasc Biol 1996; 16: 539-45.
14 Grancha S, Estellés A, Falcó C, Chirivella M, España F, Aznar J. Detailed localization of type 1 plasminogen activator inhibitor mRNA expression and antigen in atherosclerotic plaque on human coronary artery. Fibrinol Proteol 1998; 12: 53-61.
15 Alessi M, Juhan-Vague I, Kooistra T Declerck, Collen D. Insulin stimulates the synthesis of plasminogen activator inhibitor-1 by the human hepatocellular cell line HepG2. Thromb Haemost 1988; 60: 491-4.
16 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.
17 Dawson S, 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 (PAI-1) gene respond differently to interleukin-1 in hepG2 cell. J Biol Chem 1993; 268: 10739-45.
18 Eriksson P, Nilsson L, Hamsten A. Very-low-density lipoprotein response element in the promoter region of human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemias. Arterioscler Thromb Vasc Biol 1997; 18: 20-6.
19 Mansfield MW, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes. Thromb Haemost 1995; 74: 1032-4.
20 Margaglione M, Cappucci G, Colaizzo D, Giulani N, Vecchione G, Grandone E, Pennelli O, Di Minno G. The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol 1998; 18: 152-6.
21 Ossei Gerning N, Mansfield MW, Stickland MH, Wilson IJ, Grant PJ. Plasminogen activator inhibitor-1 promoter 4G/5G genotype and plasma levels in relation to a history of myocardial infarction in patients characterized by coronary angiography. Arterioscler Thromb Vasc Biol 1997; 17: 33-7.
22 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP, Arveiler D, Henney AM, Cambien F. 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. Thromb Haemost 1995; 74: 837-41.
23 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Miletich JP. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997; 95: 59-62.
24 Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost 1995; 74: 842-7.
25 Grubic N, Stegnar M, Peternel P, Kaider A, Binder BR. A novel G/A and the 4G/5G polymorphism within the promoter of the plasminogen activator inhibitor-1 gene in patients with deep vein thrombosis. Thromb Res 1996; 84: 431-43.
26 Nordenhem A, Wiman B. Plasminogen activator inhibitor-1 (PAI-1) content in platelets from healthy individuals genotyped for the 4G/5G polymorphism in the PAI-1 gene. Scand J Clin Lab Invest 1997; 57: 453-62.
27 Burzotta F, DiCastelnuovo A, Amore C, D’Orazio A, Di Bitondo R, Donati MB, Iacoviello L. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in Italians: a model of gene-enviroment interaction. Thromb Haemost 1998; 79: 354-8.
28 Margaglione M, Cappucci G, D’Addedda M, Colaizzo D, Giuliani N, Vecchione G, Mascolo G, Grandone E, Di Minno G. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis. Arterioscler Thromb Vasc Biol 1998; 18: 562-7.
29 Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, Szklo M. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993; 328: 1069-75.
30 The writing group for the PEPI trial. Effects of estrogen or estrogen/ progestin regimens on hearth disease risk factors in postmenopausal women: the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 1995; 273: 199-208.
31 Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335: 453-61.
32 Gilabert J, Estellés A, Cano A, España F, Barrachina R, Grancha S, Aznar J, Tortajada M. The effect of estrogen-replacement therapy with or without progestogen on the fibrinolytic system and coagulation inhibitors in postmenopausal status. Amer J Obstet Gynecol 1995; 173: 1849-54.
33 Meade TW. Hormone replacement therapy and haemostatic function. Thromb Haemost 1997; 78: 765-9.
34 Gebara OCE, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Welty FK, Wilson PWF, Levy D, Muller JE, Tofler GH. Association between increased estrogen status and increased fibrinolytic potential in the Framingham offspring study. Circulation 1995; 91: 1952-8.
35 Estellés A, Gilabert J, Aznar J, Loskutoff DJ, Schleef R. Changes in the plasma levels of type 1 and type 2 plasminogen activator inhibitors in normal pregnancy and in patients with severe preeclampsia. Blood 1989; 74: 1332-8.
36 Falk G, Almquist A, Nordenhem A, Suensson H, Wiman B. Allele specific PCR for detection of a sequence polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene. Fibrinolysis 1995; 9: 170-4.
37 Mansfield MW, Stickland MH, Grant PJ. PAI-1 concentrations in first-degree relatives of patients with non-insulin-dependent diabetes: metabolic and genetic associations. Thromb Haemost 1997; 77: 357-61.
38 Mannucci PM, Mari D, Merati G, Peyvandi MF, Tagliabue L, Sacchi E, Taioli E, Sansoni P Bertolini, Franceschi C. Gene polymorphisms predicting high plasma levels of coagulation and fibrinolysis proteins. A study in centenarians. Arterioscler Thromb Vasc Biol 1997; 17: 755-9.
39 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.
40 Henry M, Chomiki N, Scarabin PY, Alessi MC, Peiretti F, Arveiler D, Ferrieres J, Evans A, Amouyel P, Poirier O, Cambien F, Juhan-Vague I. Five frequent polymorphisms of the PAI-1 gene. Lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. Arterioscler Thromb Vasc Biol 1997; 17: 851-8.
41 Hong Y, Pedersen NL, Egberg N, de Faire U. Moderate genetic influences on plasma plasminogen activator inhibitor-1 and evidence of genetic and environmental influences shared by plasminogen activator inhibitor-1, triglycerides, and body mass index. Arterioscler Thromb Vasc Biol 1997; 17: 2776-82.
42 Humphries SE, Panahloo A, Montgomery HE, Green F, Yudkin J. Gene-environment interaction in the determination of levels of haemostatic variables involved in thrombosis and fibrinolysis. Thromb Haemost 1997; 78: 457-61.
43 Henry M, Tregouët DA, Alessi MC, Aillaud MF, Visvikis S, Siest G, Tiret L, Juhan-Vague I. Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen concentrations. A family study with part of the Stanislas cohort. Arterioscler Thromb Vasc Biol 1998; 18: 84-91.
44 Zöller B, Garcia de Frutos P, Dahlbäck B. A common 4G allele in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene as a risk factor for pulmonary embolism and arterial thrombosis in hereditary protein S deficiency. Thromb Haemost 1998; 79: 802-7.
45 Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997; 17: 3071-8.