Table 3 Genotype distribution of PAI-1 4G/5G polymorphism among various cohorts (percentages)

n PAI-1 4G/4G PAI-1 4G/5G PAI-1 5G/5G Country of origin of study participants Ridker et al. [20] 495 133±26.9 247±49.9 115±23.2 United States Mannucci et al. [21] 254 81±31.9 128±50.4 43±16.9 Italy Kimura et al. [14] 543 189±34.8 269±49.5 85±15.7 Japan Henry et al. [22] 858 222±25.9 439±51.2 197±23.0 France Grancha et al. [23] 41 6±14.6 23±56.1 12±29.3 Spain Ossei-Gerning et al. [24] 453 130±30.0 210±48.0 94±22.0 United Kingdom Roest et al. [25] 498 146±29.3 259±52.0 93±18.7 The Netherlands

farction, which is intriguing as high PAI-1 is considered a predictor of myocardial infarction in young men [18]. Despite this fact, the corresponding genetic marker is more frequent in the studied subjects who have escaped major age-related atherothrombotic disease and reached old age.

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Nevertheless, it must be considered that the 4G allele which might be associated with higher PAI-1 serum lev- els is not necessarily a disadvantageous marker. The ac- tivity of the fibrinolytic system is reflected in circulating levels of tissue-type plasminogen activator (t-PA) and its most important inhibitor, PAI-1. Elevated t-PA antigen levels are strongly associated with elevated PAI-1 anti- gen and activity [26]. Increased levels of t-PA antigen have been shown to be a marker of risk of several thromboembolic diseases [27, 28]. The pathophysiologi- cal background of this finding is controversial; one pos- sible mechanism is the increased risk of arteriosclerotic plaque rupture under conditions of an enhanced fibrinol- ysis. Thus individuals with the 4G/4G allele may better balance increases in t-PA levels, and this could represent a possible mechanism for reduced fibrinolytic activity to be advantageous. This hypothesis is supported by evi- dence that thrombosis increases the expression and cir- culating levels of PAI-1 [29, 30].