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Proc. Natl. Acad. Sci. USA Vol. 92, pp. 1851-1855, March 1995 Medical Sciences

Allele-specffic increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction
PER ERIKSSON*, BENGT KALLIN, FERDINAND M. VAN 'T HOOFT, PETER BAVENHOLM,
AND ANDERS HAMSTEN
Atherosclerosis Research Unit, King Gustaf V Research Institute, Department ofMedicine, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden

Communicated by Victor Mutt, Karolinska Institute, Stockholm, Sweden, November 9, 1994 (received for September 10, 1994)

ABSTRACT Increased plasminogen-activator inhibitor 1 (PAI-1) activity is a common finding in patients with coronary heart disease. Here we provide evidence for an independent, etiological role of PAI-1in myocardial infarction. The 4G allele of a recently described common 4/5-guanine-tract (4G/5G) polymorphism in the PAI-i promoter is associated with higher plasma PAI-1 activity. The prevalence of the 4G allele is significantly higher in patients with myocardial infarction before the age of 45 than in population-based controls (allele frequencies of 0.63 vs. 0.53). Both alleles bind atranscriptional activator, whereas the 5G allele also binds a repressor protein to an overlapping binding site. In the absence of bound repressor, the basal level of PAI-i transcription is increased.
Reduced fibrinolytic capacity, mainly due to increased plasminogen-activator inhibitor 1 (PAI-1) activity in plasma, is a common finding in patients with coronary heart disease (CHD) (1). Poor fibrinolyticactivity has also been linked to increased risk of future cardiovascular events in men aged 40-54 years participating in a prospective epidemiological study (2). Increased PAI-i is thought to predispose to coronary thrombosis due to its role as a rapid inhibitor of tissuetype plasminogen activator, the major proteolytic activator of plasminogen. Moreover, increased PAI-1 expression has beendemonstrated in atherosclerotic plaques (3, 4) suggesting that PAI-1 may play a role in atherogenesis as well. However, the clinical evidence for a cause-and-effect relationship between PAI-1 activity and CHD is still limited and confined to a few longitudinal cohort studies ofyoung post infarction patients (5, 6) and patients with CHD or peripheral atherosclerosis (7). Further, in mice transgenic for thePAI-1 gene, increased PAI-1 was shown to contribute to the development of venous but not arterial occlusions (8). Recently, the effects of gene inactivation of fibrinolytic components in mice have been studied. Mice with combined tissue-type and urokinase-type PA deficiency suffered from extensive spontaneous fibrin deposition with an associated shortened lifespan (9). Disruption of the PAI-1gene induced a mild hyperfibrinolytic state and a greater resistance to venous thrombosis (10). In the present study, we provide evidence for an independent, etiological role of PAI-1 in CHD on the basis of clinical and molecular biological studies of a common 4/5-guaninetract (4G/5G) polymorphism in the PAI-1 promoter (11) (see Fig. la). The 4G allele of this polymorphism was found to be associatedwith higher plasma PAI-1 activity, and the prevalence of the 4G allele was significantly higher in young patients with myocardial infarction. Furthermore, the 4G allelespecific increase in plasma PAI-1 activity is related to a differential binding of transcription factors to the polymorphic site which increases the basal PAI-1 transcription.
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MATERIALS AND METHODS Subjects. A total of 94 men with a first myocardial infarction
before the age of 45 were included in the study. They belonged to a consecutive series of 131 male patients who were admitted to the 10 hospitals in the...