Published online before print November 20, 2003, doi: 10.1161/01.STR.0000103831.56586.4F
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(Stroke. 2003;34:2828.)
© 2003 American Heart Association, Inc.
Original Contributions |
Editorial Comment— Genetic Make-Up for Increased PAI-1 Expression Protects Against Stroke
Research Laboratory of the Department of Clinical Chemistry, Utrecht University Medical School, Utrecht, the Netherlands
Department of Internal Medicine, Utrecht University Medical School, Utrecht, the Netherlands
This issue of Stroke reports findings that the 4G variant of the PAI-1 4G/5G polymorphism is associated with a reduced incidence of stroke.1 Those findings are in agreement with 7 other studies that observed a similar relationship between the 4G variant of PAI-1 and a reduced stroke risk.2–8 This consistency in 8 independent studies minimizes the possibility that the relationship between the PAI-1 4G variant of PAI-1 and reduced stroke risk is a chance finding.
PAI-1 4G/5G is an interesting "functional" polymorphism because the alleles are the real cause of variation in PAI-1 expression.9 The 4G allele of the PAI-1 4G/5G polymorphism lacks a binding site for a transcription repressor protein, which is present on the 5G allele. Therefore, the 4G is the high PAI-1 expresser allele and the 5G the low expresser allele. Subjects who are homozygous for the 4G allele have 25% higher plasma concentrations than subjects homozygous for the 5G allele.9 Those findings indicate that homozygosity for the 4G allele stands for lifelong exposure to increased PAI-1 expression. The PAI-1 4G/5G polymorphism is an important tool in investigating the etiological involvement of PAI-1 in stroke because genetic make-up is fixed at conception; therefore, an association between genetic make-up for increased PAI-1 expression (PAI-1 4G allele) and a reduced risk of stroke is not confounded by other risk factors of stroke.10 For the same reason, genetic make-up for high PAI-1 expression is not a consequence of stroke. A relationship between the PAI-1 4G allele and a reduced risk of stroke is therefore causal evidence for a protective role of PAI-1 against stroke.
The notion that PAI-1 protects against stroke is further supported by findings in large cohort studies that tPA levels predict an increased incidence of stroke,11,12 while plasma PAI-1 concentrations seem not associated with stroke risk.13 Still, careful consideration is required to draw definite conclusions from observational studies on the relationship between tPA or PAI-1 levels and stroke incidence because plasma variations of tPA and PAI-1 depend on estrogen levels, the renin-angiotensin system, VLDL levels, unsaturated fatty acids content, insuline-like molecules, and pro-inflammatory cytokines (reviewed in Kohler and Grant14). Therefore, a relationship between tPA or PAI-1 levels and stroke is subject to confounding by such factors.14
Until recently, PAI-1 was considered as a potentially harmful factor in stroke etiology because PAI-1 was best known for its antifibrinolytic properties.14 New insights from transgenic mice models show that the involvement of PAI-1 in stroke is more complicated because PAI-1 is involved in both harmful and protective steps in arterial disease etiology.15–19 An important protective function of PAI-1 is the inhibition of the activation of matrix-degrading enzymes in the atherosclerotic plaque, thereby preventing cardiac rupture followed by an ischemic infarction.18 Furthermore, PAI-1 is necessary to protect against tPA, which may cause local damage in the neurological tissue after an ischemic stroke.15
In conclusion, 8 independent studies observed that genetic make-up for increased PAI-1 expression protects against stroke.1–8 Those reproducible genetic associations can be considered as causal evidence that genetic make-up for increased PAI-1 expression protects against stroke because genotype is not subject to confounding and is not a consequence of stroke. The protective involvement of PAI-1 in stroke needs to be investigated further, but the properties of PAI-1 to prevent plaque rupture and protect against neurological damage after an ischemic infarction are both plausible pathways.
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