Significant impact of the presence of type 2 diabetes on the cardiovascular risk conferred by the plasminogen activator inhibitor-1–675 5G/4G polymorphism

Abstract

Background/Aims: The -675 5G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene has been associated with increased plasma levels of PAI-1 and, in some studies, with increased vascular risk. Hardly any data on the vascular risk conferred by this polymorphism are available for patients with type 2 diabetes (T2DM). We therefore aimed at investigating i) the association of this polymorphism with angiographiaclly diagnosed coronary artery disease (CAD) and ii) its impact on future vascular events in patients with T2DM and in nondiabetic individuals. Methods: Genotyping was performed in 672 consecutive Caucasian patients (463 men and 209 women, mean age 62±10 years) undergoing coronary angiography for the evaluation of stable CAD. Prospectively, we recorded vascular events over 4 years. Results: The prevalence rates of the 5G/5G, the 5G/4G, and the 4G/4G genotypes were 17.6%, 52.7%, and 29.7% in patients with T2DM (n=148) and 23.5%, 48.3%, and 28.2% in non-diabetic subjects (n=524). In non-diabetic subjects the homozygote PAI-1 4G4G genotype after adjustment for age, gender, hypertension, smoking, BMI, LDL cholesterol, and HDL cholesterol was significantly associated with significant stenoses (adjusted odds ratio (OR) 1.77 [95% CI 1.13–2.78], p=0.013), whereas no such association was observed in patients with T2DM (OR 0.81 [0.34–1.93]; p=0.635). An interaction term T2DM x 4G4G genotype was significant (p=0.026), indicating that the association of the polymorphism with CAD was significantly stronger in non-diabetic subjects than in patients with T2DM. Also prospectively, the 4G4G genotype conferred an increased risk of vascular events in non-diabetic subjects but not in T2DM patients, with hazard ratios of 1.66 [1.05–2.64], p=0.031 and 0.72 [0.33–1.60], p=0.423, respectively (adjusted for age, gender, hypertension, smoking, BMI, LDL cholesterol, and HDL cholesterol). Again, an interaction term T2DM x 4G4G genotype was significant (p=0.042). Conclusions: We conclude that presence of T2DM significantly modulates the vascular risk conferred by the PAI-1–675 5G/4G polymorphism.