Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary arterydisease - Influence of hormone replacement therapy

Increased circulating levels of type 1 plasminogen activator inhibitor (PAI -1) have been associated with coronary artery disease (CAD). However, genet ic and environmental determinants of PAI-1 expression are only partially un derstood. The levels of PAI-1 have been found to relate to 4/5 guanosine (4 G/5G) polymorphism in the promoter region of the PAI-1 gene. The 4G allele in this polymorphism has been associated with higher levels of plasma PAI-1 activity, but despite the strong correlation between PAI-1 activity and an tigen, no association has been found between PAI-1 antigen levels and the P AI-1 promoter 4G/5G genotype. The aim of the present study was to analyze t he influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels in postme nopause women with coronary disease in comparison with healthy women in pre and postmenopausal status, and the influence of this genotype on variation s in PAI-1 levels after hormone replacement therapy (HRT). No differences b etween 4G/5G allele distribution in the groups studied were observed. The g roup of postmenopausal women with CAD showed significantly increased PAI-1 antigen and activity levels in comparison with the control groups, and the levels of PAI-1 correlated with the 4G/5G genotype. A multivariate analysis revealed that in the CAD group there was a high correlation between 4G all ele dosage and PAI-1 antigen levels, which were also influenced by the trig lyceride levels but not by estrogen or glucose levels. After hormone replac ement therapy the decrease in PAI-1 levels was correlated with the 4G allel e dosage. We conclude that in the group of postmenopausal women with CAD th e influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels is more ev ident than in the control groups, and that the decrease in PAI-1 levels aft er HRT in CAD women correlates with the 4G allele dosage.