Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women.
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.


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.
Roest
M
M
Julius Center for Patient Oriented Research, Department of Hematology, Graduate School of Biomembranes, Utrecht University Medical School, Netherlands. M.Roest@jc.azu.nl
van der Schouw
Y T
YT
Banga
J D
JD
Tempelman
M J
MJ
de Groot
P G
PG
Sixma
J J
JJ
Grobbee
D E
DE
D000367:Age Factors; D000368:Aged; D002318:Cardiovascular Diseases / Q000235:genetics / Q000401:mortality; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000401:mortality*; D015331:Cohort Studies; D004247:DNA / Q000652:urine; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000401:mortality; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D017698:Postmenopause; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013997:Time Factors
D017395:Plasminogen Activator Inhibitor 1; D004247:DNA