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- Andersson, Malin E, 1978, et al.
(författare)
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Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease.
- 2007
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Ingår i: International journal of molecular medicine. - 1107-3756 .- 1791-244X. ; 20:2, s. 233-9
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Tidskriftsartikel (refereegranskat)abstract
- Kinesin is a microtubule-associated motor protein that transports Alzheimer-associated amyloid precursor protein (APP) in neurons. In animal models, impaired kinesin-mediated APP transport seems to enhance formation of the neurotoxic 42 amino acid fragment of beta-amyloid (A beta 42). In man, one study suggests that a polymorphism (rs8702, 56,836G>C) in the kinesin light chain 1 gene (KNS2) may affect the risk of Alzheimer's disease (AD). To further assess KNS2 as a susceptibility gene for AD we analyzed 802 patients with sporadic AD and 286 controls, 134 longitudinally followed patients with mild cognitive impairment (MCI) and 39 cognitively stable controls for the rs8702 polymorphism. The rs8702 polymorphism did not influence risk of AD (p=0.46). However, rs8702 interacted with APOE epsilon 4 carrier status in AD (p=0.006) and influenced cerebrospinal fluid levels of hyperphosphorylated tau in MCI patients who converted to AD during follow-up (p=0.018). These findings support earlier indications that genetic variability in the KNS2 gene may play a role during early stages of AD pathogenesis.
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- 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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- 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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- 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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- Jood, Katarina, 1966
(författare)
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Risk factors in ischemic stroke
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ischemic stroke is a complex disease in which environmental and genetic factors make about equal contributions to the etiology. However, knowledge regarding the molecular basis of the genetic influence and the impact of specific lifestyle factors is limited. Hypertension, diabetes, and smoking have been identified as major risk factors, but data for the different ischemic stroke subtypes are incomplete. Potential novel vascular risk factors, such as hemostasis, have mainly been investigated in relation to coronary heart disease, and associations to stroke remain to be established. The aim of the present thesis was therefore to study risk factors for ischemic stroke with focus on genetics, fibrinolysis, and lifestyle.The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) was designed for genetic association studies. Six hundred patients with ischemic stroke before the age of 70 years, and 600 matched population controls were recruited. Great emphasize was put on classification of ischemic stroke subtypes, as we hypothesized that their risk factor profiles may differ. Accordingly, we found that the associations for established risk factors differed by subtype. Furthermore, family history of stroke was independently associated with overall ischemic stroke, large vessel disease (LVD), small vessel disease (SVD), and cryptogenic stroke, but not with cardioembolic (CE) stroke. Lifestyle factors were investigated prospectively in a cohort of 7,402 men. After 28 years of follow-up, we found an independent association between increased body mass index and ischemic stroke. Self-perceived psychological stress showed independent association with total stroke (i.e. ischemic and hemorrhagic stroke combined), but no significant association was found when the two stroke types were analyzed separately. Self-perceived psychological stress was further investigated in SAHLSIS. An independent association with overall ischemic stroke, LVD, SVD, cryptogenic stroke, but not with CE stroke was found. The importance of endogenous fibrinolysis was investigated using genetic markers for the expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1), i.e. the t-PA -7,351C>T and the PAI-1 -675 4G>5G polymorphism. When analyzed as independent covariates, neither of the two genetic variants showed significant association with ischemic stroke. However, a protective effect for the t-PA CC/PAI-1 4G4G genotype combination (i.e. corresponding to high t-PA and high PAI-1 expression) was observed. We also investigated the pattern of acute t-PA release in a smaller experimental study. Compared to controls, patients with ischemic stroke showed a preserved, but delayed, acute t-PA release.In conclusion, we found distinct differences in risk factor patterns for the ischemic stroke subtypes. This was true for both established and novel risk factors, which highlights the importance of subtype characterization in stroke research. Regarding the fibrinolytic system, we found a protective effect of the t-PA CC/PAI-1 4G4G genotype combination, suggesting a gen-gen interaction and a complex role for t-PA and PAI-1 during brain ischemia.
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