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Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke: replicated findings in two nested case-control studies based on independent cohorts.
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
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2005 (English)In: Stroke, ISSN 0039-2499, Vol. 36, no 8, 1661-1665 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2005. Vol. 36, no 8, 1661-1665 p.
Keyword [en]
Adult, Aged, Alleles, Blood Pressure, Case-Control Studies, Cerebrovascular Accident/diagnosis/*genetics, Cohort Studies, Gene Frequency, Genetic Predisposition to Disease, Genotype, Heterozygote, Homozygote, Humans, Ischemia, Middle Aged, Odds Ratio, Plasminogen Activator Inhibitor 1/*genetics/physiology, Polymorphism; Genetic, Promoter Regions (Genetics), Regression Analysis, Risk, Risk Factors, Sweden, Time Factors, Transcription; Genetic, Triglycerides/metabolism
URN: urn:nbn:se:umu:diva-15042DOI: 10.1161/01.STR.0000174485.10277.24PubMedID: 16020771OAI: diva2:154714
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-11-30Bibliographically approved
In thesis
1. Genetic aspects of stroke: association and linkage studies in a northern Swedish population
Open this publication in new window or tab >>Genetic aspects of stroke: association and linkage studies in a northern Swedish population
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stroke is a common, multifactorial cardiovascular disease. A stroke event is the result of traditional risk factors (i.e. hypertension, diabetes, smoking), environmental exposures and genetic factors in a complex interplay. The genetic contribution is, as estimated by studies on the influence of family history on the risk of stroke, limited on the individual level, and overridden by, for example the excess risk associated with smoking. On the population level, and as a means to better understand the etiology of stroke, genetics can play a major role.

Northern Sweden is well suited for studying the genetic aspects of stroke. The population shows signs of founder effects, and is relatively homogeneous. Large-scale cardiovascular health surveys, the MONICA Project and the Västerbotten Intervention Program, allow studies on risk factors in relation to stroke. Two prospective nested case-referent study samples, (113 cases and 226 controls; 275 cases and 549 controls), and a set of 56 families (117 affected) were collected for functional candidate gene association, and linkage, studies.

The selected candidate genes included haemostatic factors and genes within the renin angiotensin system (RAS). Functional single nucleotide polymorphisms (SNPs) that influence the levels of PAI-1 (PAI-1 4G/5G), and tPA (tPA -7,351C>T), have been identified. The angiotensin converting enzyme insertion/deletion polymorphism (ACE I/D) has been shown to be associated with ischaemic stroke. The angiotensin II receptor type 1 A1166C polymorphism (AT1R A1166C), less extensively studied, has been suggested to be associated with stroke, and to interact with the ACE I/D.

We found that the PAI-1 4G/4G genotype was associated with an increased risk of future ischaemic stroke (OR 1.79, 95%CI 1.01-3.19), and this was replicated in a second study sample. Furthermore, levels of serum triglycerides modulated the effect of the genotype. In the study on tPA, no association between the tPA -7,351C>T polymorphism and the risk of stroke was found in an analysis of the two study samples pooled. The two RAS polymorphisms were prospectively associated with ischaemic stroke independently of each other and other risk factors (OR 1.60, p=0.02 and OR 1.60, p=0.04, respectively).

A candidate region linkage study, focusing on a previously reported stroke susceptibility locus on chromosome 5, was performed in a set of families. In addition, association between ischemic stroke and the positional candidate gene phosphodiesterase 4D (PDE4D) was tested. Linkage to 5q12 was replicated in this independent population, but not PDE4D association with stroke. This suggests that alternative genotypes in this stroke susceptibility locus contribute in different populations.

In conclusion, the genetic component in the causation of stroke was investigated. The results of the functional candidate gene association studies showed (1) interaction between PAI-1 genotype and a putatively modifiable risk factor, triglycerides, (2) a prospective testing of the tPA SNP with no association detected, and (3) a novel, hypothesis-generating, finding in the case of AT1R polymorphism and the risk of ischaemic stroke. The replication of linkage to chromosome 5q12 in our northern Swedish population was interesting, and it will be further explored.

Place, publisher, year, edition, pages
Umeå: Folkhälsa och klinisk medicin, 2005. 52 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 999
Internal medicine, stroke, genetics, polymorphism, association, linkage, risk factors, plasminogen activator inhibitor-1, tissue plasminogen activator, angiotensin converting enzyme, angiotensin II receptor type 1, phosphodiesterase 4D, Invärtesmedicin
National Category
Clinical Medicine
Research subject
urn:nbn:se:umu:diva-668 (URN)91-7305-999-4 (ISBN)
Public defence
2006-01-20, Sal B, 9 tr, Tandläkarhöskolan, Umeå, 09:00 (English)
Available from: 2005-12-29 Created: 2005-12-29 Last updated: 2016-08-22Bibliographically approved

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