(Circulation. 2000;101:67.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Plasminogen Activator Inhibitor 4G Polymorphism Is Associated With Decreased Risk of Cerebrovascular Mortality in Older Women
From the Julius Center for Patient Oriented Research (M.R., Y.T.v.d.S., D.E.G.); Department of Hematology, Graduate School of Biomembranes (M.R., M.J.T., P.G.d.G., J.J.S.); and Department of Internal Medicine (M.R., J.D.B.), Utrecht University Medical School, Utrecht, The Netherlands.
Correspondence to Mark Roest, MSc, Julius Center for Patient Oriented Research, Utrecht University Medical School, Heidelberglaan 100, 3584 CX Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands. E-mail M.Roest{at}jc.azu.nl
Background—A common 4G allele of a 4G/5G polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with increased transcription of the PAI-1 protein, which may lead to decreased fibrinolysis. It has therefore been proposed as a candidate risk factor for myocardial infarction or stroke.
Methods and Results—We studied the relationship between PAI-1 4G/5G genotype and the risk of cardiovascular mortality in a prospective cohort study among 12 239 women initially aged between 52 and 67 years, with a maximum follow-up time of 18 years (153 732 follow-up years). PAI-1 4G/5G genotype was measured in DNA obtained from urine samples, which were collected at baseline, of 498 women who died of a cardiovascular disease and a random sample of 512 women from the same cohort who did not die of cardiovascular disease. The PAI-1 4G/5G genotype was not associated with risk of myocardial infarction or other cardiovascular mortality. However, PAI-1 4G4G homozygotes had a markedly reduced risk of cerebrovascular mortality compared with PAI-1 5G5G homozygotes: the relative risk was 0.4, with a 95% CI of 0.2 to 0.7, whereas the relative risk of cerebrovascular mortality in PAI-1 4G5G heterozygotes compared with PAI-1 5G5G homozygotes was 0.7, with a 95% CI of 0.4 to 1.1.
Conclusions—These findings are suggestive of an important contribution of PAI-1 in cerebrovascular pathology, probably via pathways other than fibrinolysis. PAI-1 may protect against destabilization of the atherosclerotic plaque, or it may inhibit neurotoxicity of tissue plasminogen activator in the brain.
Key Words: plasminogen activators • cerebrovascular disorders • mortality
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