| 1. |
- Jood, Katarina, 1966, et al.
(författare)
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Fibrinolytic gene polymorphism and ischemic stroke
- 2005
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 36:10, s. 2077-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: The tissue-type plasminogen activator (tPA) -7351C>T and the plasminogen activator inhibitor type 1 (PAI-1) -675 4G>5G polymorphisms influence transcriptional activity. Both variants have been associated with myocardial infarction, with increased risk for the T and 4G allele, respectively. In this study we investigated the possible association between these polymorphisms, the respective plasma protein levels, and ischemic stroke. METHODS: In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 patients with acute ischemic stroke aged 18 to 69 years and 600 matched community controls were recruited. Stroke subtype was determined using Trial of Org 10172 in Acute Treatment criteria. RESULTS: There were no associations between individual genetic variants and ischemic stroke. The multivariate-adjusted odds ratio for overall ischemic stroke was 1.11 (95% CI 0.87 to 1.43) for tPA T allele carriers, and 0.84 (95% CI, 0.64 to 1.11) for subjects homozygous for the PAI-1 4G allele. When genotypes were combined, a protective effect for the tPA CC/PAI-1 4G4G genotype combination was observed (odds ratio 0.65, 95% CI 0.43 to 0.98; P<0.05). Plasma levels of tPA and PAI-1 antigen at follow-up were independently associated with overall ischemic stroke. tPA-antigen differed by stroke subtype and was highest among those with large-vessel disease and cardioembolic stroke. CONCLUSIONS: Neither the tPA -7351C>T nor the PAI-1 to 675 4G>5G polymorphism showed significant association with ischemic stroke. For the tPA CC/PAI-1 4G4G genotype combination, a protective effect was observed. Collectively, these results are consistent with a more complex role for tPA and PAI-1 in the brain as compared with the heart.
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| 2. |
- Ladenvall, Claes, 1974, et al.
(författare)
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Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype
- 2006
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 37:8, s. 2018-23
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: C-reactive protein (CRP) has evolved as an inflammatory risk marker of cardiovascular disease. Several single-nucleotide polymorphisms at the CRP locus have been found to be associated with CRP levels. The aim of the present study was to investigate CRP levels and genetic variants in etiological subtypes of ischemic stroke. METHODS: The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 consecutive ischemic stroke cases (18 to 69 years) and 600 matched controls from western Sweden. Stroke subtypes were defined by the TOAST classification. Serum CRP levels were determined by a high-sensitivity immunometric assay. RESULTS: CRP levels were significantly higher for all ischemic stroke subtypes compared with controls, both in the acute phase and at the 3-month follow-up. After adjustment for traditional risk factors, CRP at follow-up was related to higher odds ratios (ORs) of overall ischemic stroke (OR, 1.25; 95% CI, 1.09 to 1.43) and large-vessel disease (OR, 1.48; 95% CI, 1.09 to 2.00). The CRP -286C>T>A, 1059G>C, and 1444C>T single-nucleotide polymorphisms showed significant associations with CRP levels. However, neither CRP genotypes nor haplotypes showed an association to overall ischemic stroke. CONCLUSIONS: This is the first large study on CRP in different TOAST subtypes in a young ischemic stroke population. CRP levels differed between etiological subtypes of ischemic stroke both in the acute phase and at the 3-month follow-up. CRP at follow-up was associated with overall ischemic stroke and the large-vessel disease subtype. Genetic variants at the CRP locus were associated with CRP levels, but no association was detected for overall ischemic stroke.
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| 3. |
- Jood, Katarina, 1966, et al.
(författare)
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Family history in ischemic stroke before 70 years of age: the Sahlgrenska Academy Study on Ischemic Stroke
- 2005
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Ingår i: Stroke. - 1524-4628. ; 36:7, s. 1383-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Results from twin and family history studies of ischemic stroke suggest that future molecular genetic studies should focus on strictly defined stroke subtypes and younger cases. Accordingly, we investigated stroke subtypes, vascular risk factors, and family history in a large study of patients with ischemic stroke onset before age 70 years. METHODS: Six hundred consecutive white participants with ischemic stroke (18 to 69 years) and 600 age- and sex-matched controls were examined for vascular risk factors and family history of stroke and myocardial infarction (MI). Stroke subtype was defined using Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: Family history of stroke was associated with overall ischemic stroke (multivariate odds ratio [OR], 1.75; 95% confidence interval [CI], 1.26 to 2.43), large-vessel disease (LVD) (OR, 1.88; 95% CI, 1.02 to 3.44), small-vessel disease (SVD, OR, 1.79; 95% CI, 1.13 to 2.84), and cryptogenic stroke (OR, 1.70; 95% CI, 1.13 to 2.56), but not with cardioembolic stroke. Family history of MI was strongly associated with LVD (OR, 3.25; 95% CI, 1.74 to 6.07), whereas no significant association were observed for other subtypes. We also found an independent association between family history of stroke and a favorable outcome after 3 months. CONCLUSION: Family history of stroke is an independent risk factor for ischemic stroke with onset before age 70 years. For the first time to our knowledge, we report this association not only for LVD and SVD but also for cryptogenic stroke, implying that future studies of the genetics of ischemic stroke should target these 3 subtypes.
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| 4. |
- Jood, Katarina, 1966, et al.
(författare)
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Fibrinogen gene variation and ischemic stroke.
- 2008
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Ingår i: Journal of thrombosis and haemostasis : JTH. - : Elsevier BV. - 1538-7836. ; 6:6, s. 897-904
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Plasma fibrinogen level and fibrin clot structure are heritable traits that may be of importance in the pathogenesis of ischemic stroke. OBJECTIVES: To investigate associations between variation in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes, fibrinogen level, and ischemic stroke. METHODS: The Sahlgrenska Academy Study on Ischemic Stroke comprises 600 cases and 600 matched population controls. Stroke subtypes were defined according to TOAST criteria. Plasma fibrinogen level was measured by an automated clot-rate assay. Eight tagging single nucleotide polymorphisms (SNPs) were selected to capture genetic variation in the FGA, FGG, and FGB genes. RESULTS: Plasma fibrinogen was independently associated with overall ischemic stroke and all subtypes, both in the acute stage (P < 0.001) and at three-month follow-up (P < 0.05). SNPs belonged to two haplotype blocks, one containing the FGB gene and the other the FGG and FGA genes. FGB haplotypes were associated with fibrinogen level (P < 0.01), but not with ischemic stroke. In contrast, FGG/FGA haplotypes showed independent association to ischemic stroke but not to fibrinogen level. In an additive model with the most common FGG/FGA haplotype (A1) as reference, the adjusted odds ratios of ischemic stroke were 1.4 [95% confidence interval (95% CI) 1.1-1.8], P < 0.01, 1.4 (95% CI 1.0-1.8), P < 0.05, and 1.5 (95% CI 1.0-2.1), P < 0.05 for the A2, A3, and A4 FGG/FGA haplotypes, respectively. CONCLUSION: FGG/FGA haplotypes show association to ischemic stroke. This association is independent of fibrinogen level, thus suggesting that the association between ischemic stroke and variation at the FGG/FGA genes is mediated by qualitative rather than quantitative effects on fibrin(ogen).
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| 5. |
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| 6. |
- Ladenvall, Claes, 1974, et al.
(författare)
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Association between factor XIII single nucleotide polymorphisms and aneurysmal subarachnoid hemorrhage Clinical article
- 2009
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Ingår i: JOURNAL OF NEUROSURGERY. - 0022-3085. ; 110:3, s. 475-481
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Tidskriftsartikel (refereegranskat)abstract
- Object Family studies have suggested a role of genetic factors in susceptibility to aneurysmal subarachnoid hemorrhage (aSAH), but the underlying genetic risk factors remain poorly defined. There is an activation of the fibrinolytic system in aSAH, and fibrinolytic markers may be useful in predicting outcome. The authors investigate associations between putative functional variants in genes of importance for fibrinolysis and aSAH and/or outcome following aSAH. Methods One hundred eighty-three patients presenting with aSAH at a neurointensive care unit were consecutively recruited. Two healthy controls per case, matched for age, sex, and geographic region, were randomly recruited. Outcome was assessed after 1 year according to the extended Glasgow Outcome Scale. Single nucleotide polymorphisms (SNPs) in the tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), and factor XIII (FXIII) genes were investigated. Results Participants carrying the FXIII 34Leu allele showed an increased risk of aSAH. When adjusting for smoking and hypertension, 2 haplotypes, differing on either the FXIII Val34Leu or the Pro564Leu position, showed an association to aSAH. No significant association was observed for the tPA -7351 C > T, PAI-1 -675 4G > 5G, or TAFI Ala147Thr SNPs. No specific SNP or haplotype was associated with outcome after aSAH, whereas a weak association was observed for a tPA/PAI-1 genotype combination. Conclusions Polymorphisms in the FXIII gene showed association to aSAH. The finding of an increased risk of bleeding in FXIII 34Leu carriers is biologically plausible.
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| 7. |
- Ladenvall, Claes, 1974
(författare)
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Genetic association studies in stroke
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stroke is the third most common cause of death and the most common cause of disability in adults in developed countries. It is a complex disease in which genetic and environmental factors make about equal contributions. A significant proportion of the environmental component remains to be elucidated and little is known about which genes that are involved. There are two main stroke types; ischemic and hemorrhagic. Both these types have several different etiological subtypes. The specific aim of the present work was to perform clinical association studies to test the hypothesis that hemostatic and inflammatory gene polymorphisms, and/or plasma levels of the respective proteins, are associated with stroke, and to investigate whether associations differ between stroke subtypes. The studies on ischemic stroke were based on the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), in which great emphasize has been put on phenotyping by physical examination and neuroimaging. The study comprises 600 consecutive ischemic stroke patients presenting with ischemic stroke before the age of 70 years and 600 matched population-based controls. Stroke patients were classified according to the main etiological subtypes of ischemic stroke, i.e. large-vessel disease (LVD), small-vessel disease (SVD), cardioembolic stroke (CE stroke) and cryptogenic stroke. The study on aneurysmal subarachnoid hemorrhage (aSAH) was based on patients admitted to the Neurointensive Care Unit, Sahlgrenska. A total of 183 patients with a confirmed aneurysmal origin of the SAH were included. Two matched population-based controls were recruited for each case. Genotyping was performed using 5´nuclease assays (TaqMan) and plasma levels of proteins were determined by immunological methods. Family history of stroke showed independent association to all ischemic stroke subtypes, except CE stroke. In our first genetic association study, the fibrinolytic pathway was studied. A reduced risk of ischemic stroke was observed for a genotype combination indicating a high gene expression level of both tissue-type plasminogen activator and plasminogen activator inhibitor type 1. This association was not detected in aSAH. However, an increased risk of aSAH was found for subjects carrying the coagulation factor XIII 34Leu allele. This variant has been shown to influence fibrinolysis by affecting the fibrin network. Family history of myocardial infarction (MI) only showed association to one ischemic stroke subtype, i.e. LVD. The explanation for this may be that atherosclerosis is a common denominator for MI and LVD. In support for this hypothesis, increased plasma levels of the inflammatory marker C-reactive protein was only found in the LVD group. This is in contrast to the fibrinolytic pathway. Plasma levels of tPA, PAI-1 and the fibrinolytic inhibitor TAFI were increased in all ischemic stroke subtypes. In conclusion, the results support a genetic contribution in stroke. This genetic contribution seems to differ between subtypes, which highlights the importance of subtype classification in stroke research. Furthermore, the findings suggest that inflammatory factors may be of more importance for developing LVD, while the fibrinolytic pathway seems to be involved in all ischemic stroke subtypes.
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| 8. |
- Ladenvall, Claes, 1974, et al.
(författare)
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Thrombin activatable fibrinolysis inhibitor activation peptide shows association with all major subtypes of ischemic stroke and with TAFI gene variation
- 2007
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Ingår i: Arterioscler Thromb Vasc Biol. - 1079-5642. ; 27:4, s. 955-62
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Thrombin activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis. The aim of the present study was to investigate the possible association between TAFI and overall ischemic stroke and ischemic stroke subtypes. METHODS AND RESULTS: The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 cases (18 to 69 years) and 600 matched population controls. Stroke subtype was defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. TAFI was investigated at the protein level, by analyzing plasma levels of intact TAFI and released activation peptide [AP], and at the genetic level, by genotyping a selection of eleven single nucleotide polymorphisms. After adjustment for traditional risk factors, both TAFI measurements showed association with overall ischemic stroke (AP: odds ratio, 2.22; 95% confidence interval, 1.89 to 2.61; intact TAFI: odds ratio, 1.21; 95% confidence interval, 1.06 to 1.38; for 1-SD increase in AP and intact TAFI, respectively). AP showed associations with all 4 major subtypes of ischemic stroke and intact TAFI to large vessel disease and cryptogenic stroke. TAFI genotypes and haplotypes showed significant associations with both TAFI measurements. In contrast, no association was observed between genetic variants and overall ischemic stroke. CONCLUSION: TAFI levels show independent association with overall ischemic stroke. This association is stronger for released AP than for intact TAFI, and for released AP, it is present in all ischemic stroke subtypes.
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