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Tissue-type plasminogen activator –7,351C>T polymorphism does not influence the risk of stroke: A prospective case-referent study
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
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(English)Article in journal (Refereed) Submitted
URN: urn:nbn:se:umu:diva-4903OAI: diva2:144180
Available from: 2005-12-29 Created: 2005-12-29 Last updated: 2016-08-22Bibliographically 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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Wiklund, Per-Gunnar
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