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

Area of Science:

• Genetics
• Cardiovascular Science
• Epidemiology

Background:

• The 4G allele of the plasminogen activator inhibitor-1 (PAI-1) gene polymorphism is linked to higher PAI-1 protein levels, potentially reducing fibrinolysis.
• This association has led to PAI-1 being investigated as a risk factor for myocardial infarction and stroke.

Purpose of the Study:

• To investigate the association between the PAI-1 4G/5G genotype and the risk of cardiovascular mortality in a large prospective cohort of women.
• To determine if the PAI-1 genotype influences the risk of myocardial infarction, stroke, or other cardiovascular mortality.

Main Methods:

• A prospective cohort study involving 12,239 women aged 52-67 years, with up to 18 years of follow-up.
• PAI-1 4G/5G genotype was determined from DNA in urine samples from 498 women who died of cardiovascular disease and 512 controls.

Main Results:

• No significant association was found between the PAI-1 4G/5G genotype and the risk of myocardial infarction or overall cardiovascular mortality.
• However, PAI-1 4G4G homozygotes showed a significantly reduced risk of cerebrovascular mortality (RR 0.4, 95% CI 0.2-0.7) compared to 5G5G homozygotes.
• Heterozygotes (4G5G) had a non-significantly reduced risk of cerebrovascular mortality (RR 0.7, 95% CI 0.4-1.1).

Conclusions:

• The PAI-1 gene polymorphism, specifically the 4G4G genotype, appears to play a role in cerebrovascular pathology, potentially through mechanisms other than fibrinolysis.
• Plausible mechanisms include protection against atherosclerotic plaque destabilization or inhibition of neurotoxicity of tissue plasminogen activator in the brain.