RSS-Feed abonnieren
DOI: 10.1055/s-0037-1614340
The 4G4G Genotype of the Plasminogen Activator Inhibitor 4G/5G Gene Polymorphism Is Associated with Coronary Atherosclerosis in Patients at High Risk for this Disease
Publikationsverlauf
Received
25. November 1998
Accepted after revision
19. April 1999
Publikationsdatum:
09. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199903/lookinside/thumbnails/10-1055-s-0037-1614340-1.jpg)
Summary
Background. Disturbances in fibrinolytic activity, such as increase in plasminogen activator inhibitor (PAI) activity, have been linked with an increased risk for coronary artery disease (CAD) and myocardial infarction (MI). Since 4G4G homozygotes of an insertion/deletion (4G/5G) gene variation in the promoter of PAI-I have been shown to have increased levels of PAI-I, we analysed the relation of this gene polymorphism to CAD and MI in a population of 2565 participants who underwent coronary angiography for diagnostic purposes.
Results. In the total sample, the PAI-I 4G/4G genotype was associated with the presence, but not with the extent of CAD. However, in a subgroup of former and present smokers (n = 1782) or of individuals with a BMI above the mean value of 26.9 kg × m-2 (n = 1269), the PAI-I 4G4G genotype was not only associated with the presence, but also with the extent of CAD, defined either by the number of diseased vessels or by the CHD score according to Gensini. This observation also applied to other high-risk groups of individuals with high BMI and hypertension (n = 869), of subjects with high fibrinogen plasma levels (> 3.53 g × 1-1, mean value) and hypertension (n = 599) and of former and present smokers with high fibrinogen and hypertension (n = 452). An association of the gene variation with MI was not detected.
Conclusions. The present data indicate that the 4G/4G genotype of the PAI-I gene polymorphism is an independent risk factor for coronary artery disease and that the additional presence of major cardiovascular risk factors accelerates the risk for this disease.
-
References
- 1 Hamsten A, Wiman B, De Faire U, Blombäck M. Increased plasma levels of a rapid in hibitor of tissue plasminogen activator in young survivors of myocardial infarction. New Engl J Med 1985; 313: 1557-63.
- 2 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-7.
- 3 Hamsten A, de Faire U, Waldius G, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
- 4 Cortellaro M, Cofrancesco E, Boscheti C. Increased fibrin turnover and high PAI-I activity as predictors of ischemic events in atherosclerotic patients: a case control study. Arterioscler Thromb 1993; 13: 1412-7.
- 5 Juhan-Vague I, Valadier J, Alessi MC, Allaud MF, Ansaldi J, Philip-Joet C, Halvoet P, Serradimigni A, Collen D. Deficient t-PA release and elevated PA inhibitor in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemost 1987; 57: 67-72.
- 6 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 (PAI-I) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-5.
- 7 Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten P. 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.
- 8 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-I (PAI-I) gene is associated with differences in plasma PAI-I activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 1995; 74: 837-41.
- 9 Dawson S, Hamsten A, Wiman B, Henney A, Humphries SE. Genetic variation at the plasminogen activator inhibitor-I locus is associated with altered levels of plasminogen activator inhibitor-I activity. Arterioscler Thromb 1991; 11: 183-90.
- 10 Mansfield MW, Stickland MH, Grant PJ. Plasminogen activator-I (PAI-I) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes. Thromb Haemost 1995; 74: 1032-4.
- 11 Ossei-Gerning N, Mansfield MW, Stickland MH, Wilson IJ, Grant PJ. Plasminogen activator inhibitor-I 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.
- 12 Colaizzo D, Margaglione M, Lirato C, Grandone E, Cappucci G, Fischetti A, Mancini FP, Pauciullo P, Di Minno G. Plasminogen activator inhibitor I 4G/5G in subjects with a history of juvenile coronary heart disease. Thromb Haemost. 1997 Suppl: 97 (Abstract).
- 13 Van der Boom JC, Bots ML, Slagboom PE, Haverkate F, Meijer P, Kluft C, Grobbee DE. The risk of smoking is modified by the 4G allele of the PAI-I gene. Thromb Haemost. 1997 Suppl: 579 (Abstract).
- 14 Margaglione M, Cappucci G, Colaizzo D, Giuliani N, Vecchione G, Grandone E, Pennelli O, Di Minno G. The PAI-I gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol 1998; 18: 152-6.
- 15 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.
- 16 Burzotta F, Di Castelnuovo A, Amore C, D’Orazio A, Donati MB, Iacoviello L. 4G/5G polymorphism in the promoter region of the PAI-I gene is not a risk factor for familial myocardial infarction: a case-control study in a sample of GISSI-2 patients. Thromb Haemost 1997; 78: 1294-5.
- 17 Sugano T, Tsuji H, Masuda H, Nakagawa K, Nishimura K, Kasahara T, Yoshizumi T, Nakahara Y, Kitamura H, Yamada K, Yoneda M, Maki K, Tatsumi T, Azuma A, Nakagawa M. Plasminogen activator inhibitor-1 promoter 4G/5G genotype is not a risk factor for myocardial infarction in a Japanese population. Blood Coagulation and Fibrinolysis 1998; 9: 201-4.
- 18 Junker R, Heinrich J, Schulte H, Tataru M, Kohler E, Schonfield R, Nowak Gottl U, Assmann G. Plasminogen activator inhibtor-1 4G/5G polymorphism and factor V Q506 mutation are not associated with myocardial infarction in young men. Blood Coagulation and Fibrinolysis 1998; 9: 597-602.
- 19 Iacoviello L, Burzotta F, Di Castelnuovo A, Zito F, Marchioli R, Donati MB. The 4G/5G polymorphism of PAI-I promoter gene and the risk of myocardial infarction: A meta-analysis. Thromb Haemost 1998; 80: 1029-30.
- 20 Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983; 51: 606.
- 21 Gardemann A, Fink M, Stricker J, Nguyen Q, Humme J, Katz N, Tillmanns H, Hehrlein FW, Rau M, Haberbosch W. ACE I/D gene polymorphism: Presence of the ACE D allele increases the risk of coronary artery disease in younger individuals. Atherosclero sis 1998; 139: 153-9.
- 22 Margaglione M, Grandone E, Cappucci G, Colaizzo D, Giulani N, Vecchione G, d’Addedda M. Di Minno An alternative method for PAI-I promoter (4G/5G) typing. Thromb Haemost 1997; 605-6.
- 23 Philips M, Juul AG, Thorsen S. Human endothelial cells produce a plasminogen activator inhibitor complex. Biochem Biophys Acta 1984; 802: 99-110.
- 24 Simpson AJ, Booth NA, Moore NR, Benneth B. Distribution of PAI-I in tissue. J Clin Pathol 1991; 44: 139-43.
- 25 Kruithof EKO, Trans-Thang C, Bachman F. Studies on the release of PAI-I from human platelets. Thromb Haemost 1987; 55: 201-5.
- 26 Booth NA, Simpson AJ, Croll A, Bennet B, Mac Gregor IR. PAI-I in plasma and platelets. Brit J Haematol 1988; 70: 327-33.
- 27 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: 185-92.
- 28 Heaton JH, Gelehrter TD. Glucocorticoid induction of plasminogen activator and plasminogen activator inhibitor messenger RNA in rat hepatoma cells. Mol Endocrinol 1989; 3: 349-55.
- 29 Nordt TK, Sawa H, Fujii S, Sobel BE. Induction of plasminogen activator inhibitor type-1 by proinsulin and insulin in vivo. Circulation 1995; 91: 764-70.
- 30 De Boer JP, Abbink JJ, Brouwer MC, Meijer C, Roem S, Voorn GP, Lambers JWJ, van Mourik JA, Hack CE. PAI-I 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: 181-5.
- 31 Dichek D, Quertermous T. Thrombin regulation of mRNA levels of tissue plasminogen activator and plasminogen activator inhibitor-I in cultured human umbilical vein endothelial cells. Blood 1989; 74: 222-8.
- 32 Gelehrter TD, Sznycer-Laszuk R. Thrombin induction of plasminogen activator inhibitor in cultured human endothelial cells. J Clin Invest 1986; 78: 1673-80.
- 33 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-I) gene. Nucleic Acids Res 1988; 16: 2805-24.
- 34 Santoso S, Kunicki TJ, Kroll H, Haberbosch W, Gardemann A. Association of the platelet glycoprotein Ia c807T gene polymorphism with myocardial infarction in younger patients. Blood 1999; 93: 2449-53.