Published Online
on November 6, 2003

A more recent version of this article appeared on December 1, 2003

This Article Full Text (PDF) All Versions of this Article: 34/12/2822    most recent 01.STR.0000098004.26252.EBv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hoekstra, T. Articles by Schouten, E. G. Search for Related Content PubMed PubMed Citation Articles by Hoekstra, T. Articles by Schouten, E. G. Related Collections Fibrinolysis Acute Cerebral Hemorrhage Acute Cerebral Infarction Genetics of Stroke Risk Factors for Stroke Epidemiology Transient Ischemic Attacks Genetics of cardiovascular disease

Submitted on June 18, 2003
Accepted on July 18, 2003

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

Tiny Hoekstra PhD; Johanna M. Geleijnse PhD^*; Cornelis Kluft PhD; Erik J. Giltay PhD; Frans J. Kok PhD; and Evert G. Schouten PhD

From the Division of Human Nutrition, Wageningen University, Wageningen (T.H., J.M.G., E.J.G., F.J.K., E.G.S.), and Gaubius Laboratory, TNO Prevention and Health, Leiden (C.K.), Netherlands.

^* To whom correspondence should be addressed. E-mail: Marianne.Geleijnse{at}wur.nl.

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]=0.4; 95% CI, 0.2 to 0.9), transient ischemic attack (RR=0.3; 95% CI, 0.1 to 0.8), and cardiovascular mortality (RR=0.5; 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 (RR=3.3 in highest versus lowest tertile; 95% CI, 1.5 to 7.1), cardiovascular mortality (RR=2.3; 95% CI, 1.2 to 4.4), and all-cause mortality (RR=1.5; 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.

Key words: cerebral ischemia, transient • cerebrovascular accident • fibrinolysis • polymorphism

This article has been cited by other articles:

				K. Jood, P. Ladenvall, A. Tjarnlund-Wolf, C. Ladenvall, M. Andersson, S. Nilsson, C. Blomstrand, and C. Jern Fibrinolytic Gene Polymorphism and Ischemic Stroke Stroke, October 1, 2005; 36(10): 2077 - 2081. [Abstract] [Full Text] [PDF]

				P.-G. Wiklund, L. Nilsson, S. N. Ardnor, P. Eriksson, L. Johansson, B. Stegmayr, A. Hamsten, D. Holmberg, and K. Asplund Plasminogen Activator Inhibitor-1 4G/5G Polymorphism and Risk of Stroke: Replicated Findings in Two Nested Case-Control Studies Based on Independent Cohorts Stroke, August 1, 2005; 36(8): 1661 - 1665. [Abstract] [Full Text] [PDF]

				D. E. Arking, G. Atzmon, A. Arking, N. Barzilai, and H. C. Dietz Association Between a Functional Variant of the KLOTHO Gene and High-Density Lipoprotein Cholesterol, Blood Pressure, Stroke, and Longevity Circ. Res., March 4, 2005; 96(4): 412 - 418. [Abstract] [Full Text] [PDF]

				M. Roest and J. D. Banga Editorial Comment-- Genetic Make-Up for Increased PAI-1 Expression Protects Against Stroke Stroke, December 1, 2003; 34(12): 2828 - 2829. [Full Text] [PDF]