PAI-1 level and the PAI-1 4G/5G polymorphism in relation to risk of non-fatal myocardial infarction

Summary

This study examines the relationship between plasma Plasminogen Activator Inhibitor-1 (PAI-1) activity and the PAI-1 4G/5G polymorphism, and their association with the risk of myocardial infarction (MI). Furthermore, this study explores whether a high level of PAI-1 or whether the PAI-1 4G/5G polymorphism synergistically interacts with any established environmental risk factor for MI. This case-referent study of subjects aged 45-70 and living in Stockholm includes 851 men and 361 women with first-time MI and 1051 men and 505 women who were randomly chosen as referents from a population register. The adjusted odds ratio (OR) of MI was 1.9 (95% confidence interval [CI] 1.4-2.8) for men with a plasma PAI-1 activity level greater than the 90^th percentile value of referents. The corresponding OR for women was 1.5 (95% CI 0.9-2.5). A strong indication of synergistic interaction was found in men for the co-exposure to high plasma PAI-1 activity and current smoking, an adjusted synergy index score of 3.9 (95% CI 1.2-13.2). In women, the 4G allele was associated slightly with an increased risk of MI, OR 1.4 (95% CI 1.0-1.9). This association was not found in men. There were no clear indications of synergistic interaction effects involving the PAI-1 4G/5G polymorphism and the environmental exposures considered (cigarette smoking, physical inactivity, overweight, diabetes mellitus, hypercholesterolaemia, hypertension, high C-reactive protein and hypertriglyceridaemia).

Keywords

Myocardial infarction - PAI-1 - 4G/5G polymorphism - interaction

• References

• 1 Wiman B, Hamsten A. The fibrinolytic enzyme system and its role in the etiology of thromboembolic disease. Semin Thromb Hemost 1990; 16 (03) 207-16.
• 2 Huber K, Christ G, Wojta J. et al. Plasminogen activator inhibitor type-1 in cardiovascular disease. Status Report 2001. Thromb Res 2001; 103 (Suppl. 01) (Suppl) S7-S19.
• 3 Folsom A. Hemostatic risk factors for atherothrombotic disease: An epidemiologic view. Thromb Haemost 2001; 86 (01) 366-73.
• 4 Franco R. Gene polymorphisms of the haemostatic system and the risk of arterial thrombotic disease. Br J Haematol 2001; 115 (03) 491-506.
• 5 Folsom A, Aleksic N, Park E. et al. Prospective study of fibrinolytic factors and incident coronary heart disease. Arterioscler Thromb Vasc Biol 2001; 21 (04) 611-7.
• 6 Juan-Vague I, Alessi M, Morange P. Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Ann Med 2000; 32 (Suppl. 01) 78-84.
• 7 Hong Y, Pedersen N, Egberg N. et al. Moderate genetic influences on plasma levels of 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 (11) 2776-82.
• 8 de Lange M, Snieder H, Ariens R. et al. The genetics of haemostasis: a twin study. Lancet 2001; 357 9250 101-5.
• 9 Dawson S, Wiman B, Hamsten A. et al. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in hepG2 cells. J Biol Chem 1993; 268: 10739-45.
• 10 Margaglione M, Cappucci G, d´Addedda M. et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis. Relation to environmental and genetic determinants. Arterioscler Thromb Vasc Biol 1998; 18 (04) 562-7.
• 11 Burzotta F, Di Castelnuovo A, Amore C. et al. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in Italians: a model of gene-environment interaction. Thromb Haemost 1998; 79: 354-8.
• 12 Mansfield M, Stickland M, Grant P. 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.
• 13 Hallqvist J, Ahlbom A, Diderichsen F. et al. How to evaluate interaction between causes: a review of practices in cardiovascular epidemiology. J Int Med 1996; 239: 377-82.
• 14 Reuterwall C, Hallqvist J, Ahlbom A. et al. Higher relative but lower absolute risk of myocardial infarction in women than in men for some major risk factors in the SHEEP study. J Int Med 1999; 246: 161-74.
• 15 Leander K, Hallqvist J, Reuterwall C. et al. Family history of coronary heart disease, a strong risk factor for myocardial infarction interacting with other cardiovascular risk factors: Results from the Stockholm Heart Epidemiology Program (SHEEP). Epidemiology 2001; 12: 215-21.
• 16 Falk G, Almqvist Å, Nordenhem A. et al. 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.
• 17 SAS procedures guide [computer program] SAS Institute Inc. 6.11; Cary, N.C: 1990
• 18 Rothman KJ, Greenland S. Modern Epidemiology. 2 ed. Philadelphia: Lippincott-Raven Publishers; 1998
• 19 Rothman KJ. Modern epidemiology. 1st ed. Boston, Mass; Little, Brown & Co: 1986
• 20 Lundberg M, Fredlund P, Hallqvist J. et al. A SAS program calculating three measures of interaction with confidence intervals. Epidemiology 1996; 7: 655-6.
• 21 Iacoviello L. The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: A meta analysis. Thromb Haemost 1998; 80 (06) 1029-30.
• 22 Ossei-Gerning N, Mansfield M, Stickland M. et al. 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 (01) 33-7.
• 23 Newby D, McLeod A, Uren N. et al. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking. Circulation 2001; 103: 1936-41.
• 24 Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med 1999; 340: 115-26.
• 25 Hamsten A, Wiman B, de Faire U. et al. 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.
• 26 Hamsten A, Walldius G, Dahlén G. et al. Serum lipoproteins and apolipoproteins in young survivors of myocardial infarction. Atherosclerosis 1986; 592: 223-35.
• 27 Ye S, Green FR, Scarabin P-Y. et al. 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. Etude CasTemo de l´infarctus du Mycocarde. Thromb Haemost 1995; 74 (03) 837-41.