Plasminogen Activator Inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in women older than fifty years of age

The 4G allele of the 4G/5G polymorphism in the promoter region of the Plasminogen Activator Inhibitor (PAI-1 4G) gene is associated with increased transcription of the PAI-1 protein compared with the 5G allele. PAI-1 is a major inhibitor of fibrinolysis and in theory the 4G allele is therefore a potential risk factor for arterial disease. The relationship between PAI 4G and cerebrovascular disease is not clear. We studied the association between PAI-1 genotype and the risk of cardiovascular disease in a prospective cohort study among 12,239 women, initially aged between 52 en 67 years with a maximum follow-up time of 18 years (168,513 follow up years). DNA was isolated from urine samples which were collected at base-line. PAI-1 4G/5G genotype is determined in 457 women who died of a cardiovascular disease and in a random sample of 452 women from the same cohort who did not die of cardiovascular disease. PAI 4G/5G genotype had no effect on the risk of myocardial infarction. Women who were homozygous for the PAI-1 4G allele had a lower risk of cerebrovascular mortality than 4G5G hétérozygotes: OR =0.54 (95% confidence interval; CI: 0.30-0.99) and than 5G homozygotes: OR=0.36 (95% CI: 0.18-0.70). The PAI-1 4G allele is associated with a decreased risk of cerebrovascular mortality in post-menopausal women. The biological explanation will probably be found in mechanisms, other than fibrinolysis, in which PAI-1 is involved.