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(Stroke. 2003;34:2822.)
© 2003 American Heart Association, Inc.

Original Contributions

4G/4G Genotype of PAI-1 Gene Is Associated With Reduced Risk of Stroke in Elderly

Tiny Hoekstra, PhD; Johanna M. Geleijnse, PhD; Cornelis Kluft, PhD; Erik J. Giltay, PhD; Frans J. Kok, PhD Evert G. Schouten, PhD

From the Division of Human Nutrition, Wageningen University, Wageningen (T.H., J.M.G., E.J.G., F.J.K., E.G.S.), and Gaubius Laboratory, TNO Prevention and Health, Leiden (C.K.), Netherlands.

Correspondence to Dr Johanna M. Geleijnse, Division of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, Netherlands. E-mail Marianne.Geleijnse{at}wur.nl

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.

Key Words: cerebral ischemia, transient • cerebrovascular accident • fibrinolysis • polymorphism

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