Published Online
on July 14, 2005

A more recent version of this article appeared on August 1, 2005

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Submitted on January 26, 2005
Revised on May 20, 2005
Accepted on May 31, 2005

Plasminogen Activator Inhibitor-1 4G/5G Polymorphism and Risk of Stroke. Replicated Findings in Two Nested Case-Control Studies Based on Independent Cohorts

Per-Gunnar Wiklund MD^*; Lennart Nilsson MD, PhD; Sofie Nilsson Ardnor MD; Per Eriksson PhD; Lars Johansson MD, PhD; Birgitta Stegmayr PhD; Anders Hamsten MD, PhD; Dan Holmberg PhD; and Kjell Asplund MD, PhD

From the Department of Public Health and Clinical Medicine (P-G.W., L.J., B.S., K.A.), Umeå University Hospital, Sweden; Atherosclerosis Research Unit (L.N., P.E., A.H.), King Gustav V Research Institute, Karolinska Hospital, Stockholm, Sweden; Department of Cardiology (L.N.), Heart Center, University Hospital, Linköping, Sweden; and Department of Medical Clinical Genetics (S.N.A., D.H.), Umeå University, Sweden.

^* To whom correspondence should be addressed. E-mail: pg.wiklund{at}medicin.umu.se.

Background and Purpose--Impaired fibrinolytic function secondary to elevated plasminogen activator inhibitor-1 (PAI-1) levels has been implicated in ischemic stroke. PAI-1 levels are determined by genetic factors and environmental factors, triglyceride levels in particular. The aim of this study was to investigate the common functional 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene and the risk of stroke.

Methods--A nested case-control study design was applied, using baseline data for 2 independent cohorts obtained at population-based surveys in northern Sweden. In study A, there were 113, and in study B, there were 275 individuals without major concomitant disease at baseline who later experienced a first-ever stroke. Blood samples obtained at baseline were analyzed for potential risk factors, including the 4G/5G polymorphism of the PAI-1 gene.

Results--The 4G allele of the PAI-1 polymorphism was associated with an increased risk of future ischemic stroke in both studies (odds ratio [OR] of 4G homozygosity, 1.87; 95% CI, 1.12 to 3.15 in study A; OR of 4G homozygosity, 1.56; 95% CI, 1.12 to 2.16 in study B). Individuals with the combination of hypertriglyceridemia and 4G homozygosity were at the greatest risk of developing stroke. Multiple logistic regression analysis identified 4G homozygosity, systolic blood pressure, and diabetes as independent predictors of ischemic stroke.

Conclusions--Identical findings in 2 independent studies strongly suggest a true and clinically important association between PAI-1 4G/5G genotype and risk of future ischemic stroke. The observed modification of the genotype effect by triglycerides may be interpreted as a gene-environment interaction.

Key words: stroke • genetics • plasminogen activator inhibitor-1 • polymorphism

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