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Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
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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.

Place, publisher, year, edition, pages
2005. Vol. 36, no 8, 1666-1671 p.
Keyword [en]
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: urn:nbn:se:umu:diva-14817DOI: 10.1161/01.STR.0000174188.04716.8dPubMedID: 16020760OAI: oai:DiVA.org:umu-14817DiVA: diva2:154489
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2017-12-14Bibliographically 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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 999
Keyword
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
Medicine
Identifiers
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)
Opponent
Supervisors
Available from: 2005-12-29 Created: 2005-12-29 Last updated: 2016-08-22Bibliographically approved
2. Genetic studies of stroke in Northern Sweden
Open this publication in new window or tab >>Genetic studies of stroke in Northern Sweden
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stroke is a common disorder of later life with a complex etiology, including both environmental and genetic risk factors. The inherited predisposition is challenging to study due to the complexity of the stroke phenotype. Genetic studies in an isolated population have successfully identified a positional candidate gene for stroke, phosphodiesterase 4D (PDE4D).

The aim of this thesis was to identify stroke susceptibility loci and positional candidate genes, taking advantage of low genetic variation in the northern Sweden population. All stroke cases were identified in a population-based stroke registry at the northern Sweden MONICA Centre. 56 families containing multiple cases of stroke and a follow up set of an additional 53 families were used for linkage studies. For association studies, 275 cases of first ever stroke together with 550 matched community controls were included. In paper I, we used a candidate region approach to investigate the PDE4D region on chromosome 5q. Linkage was obtained with a maximum allele-sharing LOD score of 2.06; P = 0.001. However, no significant association of ischemic stroke to the previously defined at-risk allele in PDE4D was observed. We next performed a genome wide linkage scan to explore new susceptibility loci for common forms of stroke (paper II). Non-parametric multipoint linkage analysis yielded allele-sharing LOD scores > 1.2 at nine locations; 1p34, 5q13, 7q35, 9q22, 9q34, 13q32, 14q32, 18p11, 20q13. The highest allele-sharing LOD score was obtained on chromosome 18p (LOD = 2.14). Fine mapping resulted in increased allele-sharing LOD scores for chromosome 5q13 and 9q22. In the follow up analysis of the nine regions, including all 109 families, the highest allele-sharing LOD scores were obtained on chromosomes 5q, 13q and 18p although none reached the initial genome wide values. In paper III, we focused on the chromosome 5q region, and further mapping and haplotype analysis in the families was performed. A common 1 cM haplotype was found to be shared among affected members of five families. In this region only the regulatory subunit 1 of phosphatidylinositol 3-kinase (PIK3R1) gene was located. Association of three single nucleotide polymorphisms in the PIK3R1 gene to common stroke was obtained in the case-control material. Finally, in paper IV, an extended pedigree containing seven families connected to common founders eight generations back was identified by genealogical analysis, and submitted to a separate genome wide scan analysis. A significant allele-sharing LOD score of 4.66 (genome wide P < 0.001) at chromosome 9q31-33 was obtained. Haplotype analysis identified a minimal common region of 3.2 cM, which was shared by four of the seven families. These four families contained all of the primary intracerebral hemorrhagic cases present in the extended pedigree.

In conclusion we have replicated linkage of stroke susceptibility to the PDE4D region on chromosome 5q, but no significant association of ischemic stroke to PDE4D was observed. Linkage analysis of stroke did not identify any new major stroke loci, indicating that multiple minor susceptibility loci in addition to the previously known locus on chromosome 5q could contribute to the disease. In the chromosome 5q region a novel positional candidate gene for stroke was identified, the PIK3R1 gene. The PIK3R1 protein has several biological actions with potential roles in stroke susceptibility. Also a novel susceptibility locus for common forms of stroke at chromosome 9q was identified in a large pedigree, which may be of special importance for susceptibility to hemorrhagic stroke.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2006. 71 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1060
Keyword
stroke, linkage, genome wide scan, susceptibility loci, association, candidade gene, PDE4D, PIK3R1, extended pedigree
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-887 (URN)91-7264-191-6 (ISBN)
Public defence
2006-10-27, Hörsal Betula, 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2009-10-23Bibliographically approved

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