An effect of the PAI-14G/5G polymorphism on cholesterol levels may explain conflicting associations with myocardial infarction and stroke

Background and Purpose: The gene- encoding plasminogen activator inhibitor type 1 ( PAI-1) has a common 4G/ 5G 'functional' polymorphism, and people homozygous for the 4G allele have higher PAI-1 plasma concentrations. The 4G/ 4G genotype is associated with increased risk of myocardial infarction but paradoxically protects against stroke. We hypothesized that this paradox may be explained via an effect of the PAI-1 polymorphism on plasma lipids. Methods: We studied 71 consecutive Italian patients referred to our Institute for first stroke or vascular cognitive impairment. PAI-1 gene 4G/ 5G polymorphism, total plasma cholesterol, plasma triglycerides, sex, age, smoking, oral contraceptive use, statin therapy, hypertension, diabetes, and history of myocardial infarction were examined. Results: The 4G/ 4G genotype was significantly associated with high cholesterol ( p = 0.003) but not with triglycerides ( p = 0.39). Adjusted odds ratios were: 5.8 for 4G/ 4G vs. 4G/ 5G ( 95% CI, 3.1 - 23.0), and 15.9 for 4G/ 4G vs. 5G/5G ( 95% CI, 2.4 - 105.0). Conclusions: This finding may explain the involvement of the PAI-1 polymorphism in the clustering of atherothrombotic risk factors, and why people with the 4G/ 4G genotype are at increased risk for myocardial infarction. Stroke is not so clearly related to hypercholesterolemia and other effects of the 4G/ 4G genotype ( perhaps increased PAI-1 expression) may protect against stroke. Copyright (c) 2006 S. Karger AG, Basel