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Genetic aspects of stroke: association and linkage studies in a northern Swedish population
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 999
Keyword [en]
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
Keyword [sv]
Invärtesmedicin
National Category
Clinical Medicine
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-668ISBN: 91-7305-999-4 (print)OAI: oai:DiVA.org:umu-668DiVA: diva2:144183
Public defence
2006-01-20, Sal B, 9 tr, Tandläkarhöskolan, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2005-12-29 Created: 2005-12-29 Last updated: 2016-08-22Bibliographically approved
List of papers
1. Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke: replicated findings in two nested case-control studies based on independent cohorts.
Open this publication in new window or tab >>Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke: replicated findings in two nested case-control studies based on independent cohorts.
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2005 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, 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.

Keyword
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
Identifiers
urn:nbn:se:umu:diva-15042 (URN)10.1161/01.STR.0000174485.10277.24 (DOI)16020771 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. Tissue-type plasminogen activator –7,351C>T polymorphism does not influence the risk of stroke: A prospective case-referent study
Open this publication in new window or tab >>Tissue-type plasminogen activator –7,351C>T polymorphism does not influence the risk of stroke: A prospective case-referent study
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(English)Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-4903 (URN)
Available from: 2005-12-29 Created: 2005-12-29 Last updated: 2017-02-13Bibliographically approved
3. Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested case-control study.
Open this publication in new window or tab >>Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested case-control study.
2008 (English)In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 26, no 7, 1367-1372 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: The renin-angiotensin system has a pathophysiological role in cardiovascular disease through a variety of processes. Polymorphisms in involved genes have been described and implicated in stroke. The aim of this study was to investigate two polymorphisms in two genes in the renin-angiotensin system and the risk of stroke. DESIGN: A nested case-control study using baseline data obtained from population-based surveys in northern Sweden was performed. There were 275 individuals without major concomitant disease who suffered a first ever stroke during follow-up and 549 controls matched for age, sex and domicile. METHODS: Blood samples obtained at baseline were analyzed for potential risk factors including the A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene and the functional insertion/deletion polymorphism of the angiotensin-converting enzyme gene. RESULTS: Individuals with the AA genotype of the AT1R gene were at increased risk of ischemic stroke (odds ratio = 1.60; P = 0.005) compared with those with the AC and CC genotypes. The D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with a higher risk of stroke (odds ratio = 1.58; P = 0.014). CONCLUSION: In this prospective study, there was an association between A1166C polymorphism in the angiotensin II receptor gene and ischemic stroke. We also replicated previous observations that the D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with increased risk of stroke. The observed elevated stroke risks conferred by these two polymorphisms are independent of each other and common risk factors such as blood pressure, diabetes, smoking and high cholesterol levels.

Identifiers
urn:nbn:se:umu:diva-21160 (URN)10.1097/HJH.0b013e3282fe1d55 (DOI)18551012 (PubMedID)
Available from: 2009-04-03 Created: 2009-04-03 Last updated: 2017-12-13
4. Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.
Open this publication in new window or tab >>Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.
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2005 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 36, no 8, 1666-1671 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Recent Icelandic studies have demonstrated linkage for common forms of stroke to chromosome 5q12 and association between phosphodiesterase4D (PDE4D) and ischemic stroke. Using a candidate region approach, we wanted to test the validity of these findings in a different population from northern Sweden. METHODS: A total of 56 families with 117 affected individuals were included in the linkage study. Genotyping was performed with polymorphic microsatellite markers with an average distance of 4.5 cM on chromosome 5. In the association study, 275 cases of first-ever stroke were included together with 550 matched community controls. Polymorphisms were tested individually for association of PDE4D to stroke. RESULTS: Maximum allele-sharing lod score in favor of linkage was observed at marker locus D5S424 (lod score=2.06; P=0.0010). Conditional logistic regression calculations revealed no significant association of ischemic stroke to the defined at-risk allele in PDE4D (odds ratio, 1.1; 95% confidence interval, 0.84 to 1.45). A protective effect may though be implied for 2 of the polymorphisms analyzed in PDE4D. CONCLUSIONS: Using a candidate region approach in a set of stroke families from northern Sweden, we have replicated linkage of stroke susceptibility to the PDE4D gene region on chromosome 5q. Association studies in an independent nested case-control sample from the same geographically located population suggested that different alleles confer susceptibility/protection to stroke in the Icelandic and the northern Swedish populations.

Keyword
3';5'-Cyclic-Nucleotide Phosphodiesterase/*genetics, Algorithms, Alleles, Case-Control Studies, Cerebrovascular Accident/genetics, Chromosome Mapping, Chromosomes; Human; Pair 5, Diabetes Complications/genetics, Exons, Family Health, Gene Frequency/*genetics, Genetic Markers, Genetic Predisposition to Disease, Genotype, Humans, Iceland, Ischemia, Linkage (Genetics), Linkage Disequilibrium, Lod Score, Microsatellite Repeats, Models; Statistical, Odds Ratio, Polymorphism; Genetic, Regression Analysis, Risk Factors, Sweden
Identifiers
urn:nbn:se:umu:diva-14817 (URN)10.1161/01.STR.0000174188.04716.8d (DOI)16020760 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2017-12-14Bibliographically approved

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