4G/4G genotype of PAI-1 gene is associated with reduced risk of stroke in elderly

Background and Purpose - Plasminogen activator inhibitor type 1 ( PAI- 1) is the main inhibitor of fibrinolysis, and high levels may increase the risk of cardiovascular disease. The 4G/ 5G polymorphism affects PAI- 1 gene transcription with lower levels of plasma PAI- 1 in the presence of the 5G allele. We investigated whether plasma PAI- 1 and 4G/ 5G genotype would predict the occurrence of cardiovascular events at old age. Methods - Relative risks for cardiovascular events and all- cause mortality were obtained in strata of PAI- 1 activity and 4G/ 5G genotype in a population- based study of 637 Dutch elderly with 7.8 years of follow- up. Results - The 4G/ 4G genotype was associated with a decreased risk of stroke ( relative risk [ RR] = 0.4; 95% CI, 0.2 to 0.9), transient ischemic attack ( RR = 0.3; 95% CI, 0.1 to 0.8), and cardiovascular mortality ( RR = 0.5; 95% CI, 0.3 to 1.0) after adjustment for age, sex, and time of blood sampling. 4G carriers had an increased risk of myocardial infarction, but this was not statistically significant. Subjects with high plasma PAI- 1 activity were at increased risk of stroke ( RR = 3.3 in highest versus lowest tertile; 95% CI, 1.5 to 7.1), cardiovascular mortality ( RR = 2.3; 95% CI, 1.2 to 4.4), and all- cause mortality ( RR = 1.5; 95% CI, 1.1 to 2.1). Conclusions - Our results provide support for a protective effect of the 4G allele against stroke, which is notable given the direct relationship between stroke and PAI- 1 activity. We hypothesize that a local increase in tissue PAI- 1 associated with the 4G allele may stabilize plaques, thereby reducing the risk of cerebrovascular disease.