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

Abstract

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]ϭ0.4; 95% CI, 0.2 to 0.9), transient ischemic attack (RRϭ0.3; 95% CI, 0.1 to 0.8), and cardiovascular mortality (RRϭ0.5; 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 (RRϭ3.3 in highest versus lowest tertile; 95% CI, 1.5 to 7.1), cardiovascular mortality (RRϭ2.3; 95% CI, 1.2 to 4.4), and all-cause mortality (RRϭ1.5; 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.

Immuno-inflammatory and thrombotic/fibrinolytic variables associated with acute ischemic stroke diagnosis

“…Until recently, PAI-1 was best known for its antifibrinolytic properties. Nevertheless, Hoekstra et al [22] reported that elevated plasma PAI-1 is a strong risk indicator for stroke at old age [21][22][23][24][25][26][27].…”

The prevalence of PAI-1 4G/5G gene variant in Serbian population

“…Some studies have shown that PAI-1 can reduce the diseases risk due to its protective action (5,7).The presence of 4G allele may lead to increased levels of PAI-1 which can cause a reduction in proteolysis and plaque stabilization during the in ammatory process in the brain tissue. Local mechanisms within brain tissue may be involved in the protective effect of PAI-1 and thereby contribute to reduced risk of stroke (5).…”

“…Local mechanisms within brain tissue may be involved in the protective effect of PAI-1 and thereby contribute to reduced risk of stroke (5). In the Dutch study, which included people aged 65 to 84 years, it has been shown that the presence of PAI-1 4G/4G genotype reduces the risk of stroke, transient ischemic attack, and death caused by the presence of cardiovascular disease (5). The inhibitory effect of PAI-1 4G/4G genotype on cell migration may lead to a reduced risk of coronary artery disease (7).…”

“…PAI-1 deluje kao inhibitor endogene  brinoliti ke aktivnosti, zbog svoje sposob-nosti da inhibira aktivnost tkivnog tipa aktivatora plazminogena (t-PA), i urokinaza tipa aktivatora plazminogena (u-PA) (4)(5)(6). Gen za PAI-1 nalazi se na hromozomu 7 (7q21.3-q22.1) i sadrži 8 introna i 9 egzona (3).…”

“…Lokalni mehanizmi unutar moždanog tkiva mogu biti uklju eni u protektivno delovanje PAI-1 i time doprineti smanjenju rizika za pojavu moždanog udara (5). U holandskoj studiji, koja je obuhvatala osobe starosti od 65 do 84 godine, pokazano je da prisustvo PAI-1 4G/4G genotipa smanjuje rizik od moždanog udara, tranzijentnog ishemijskog napada i smrtnosti usled pojave kardiovaskularne bolesti (5). Inhibitorni efekat PAI-1 4G/4G genotipa na migraciju elija može da dovode do smanjenog rizika od bolesti koronarnih arterija (7).…”