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| 2. |
- Anderson, Christopher D., et al.
(författare)
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Common Variants Within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage
- 2013
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:3, s. 612-619
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods-This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. Results-IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). Conclusions-This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. (Stroke. 2013;44:612-619.)
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| 3. |
- Andgren, S, et al.
(författare)
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Time delay between symptom and surgery in patients with carotid artery stenosis.
- 2011
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 124, s. 329-333
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Tidskriftsartikel (refereegranskat)abstract
- Andgren S, Sjöberg L, Norrving B, Lindgren A. Time delay between symptom and surgery in patients with carotid artery stenosis. Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2010.01478.x. © 2011 John Wiley & Sons A/S. Objectives - Many severe strokes are preceded by warning signs such as a transient ischemic attack or stroke with minor deficits. Carotid endarterectomy (CEA) of a symptomatic carotid artery stenosis can prevent future strokes, but should be performed within 2 weeks after the initial symptom to maximize the benefit. The aim of this study was to determine the time delays between symptom and CEA. Methods- We performed a single center observational retrospective study at a tertiary stroke center. A total of 142 carotids in 139 patients with symptomatic stenoses between 2002 and 2006 were included. The main outcome measure was time between qualifying cerebrovascular symptom and CEA. Results - The median time between symptom and CEA was 26 days. The longest delays were between the last diagnostic examination and carotid conference, and between carotid conference and surgery. The median time was shorter for those who received emergency medical care (median 21 days) and for those who were admitted immediately to hospital (median 20 days). Conclusions - The time between symptom and surgery is often longer than desirable. There are several measures to improve the chain of procedures for patients with carotid artery stenosis. These may include omitting the formal carotid conference for uncomplicated cases and minimizing waiting time for surgery.
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| 4. |
- Arsava, E. M., et al.
(författare)
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The Causative Classification of Stroke system An international reliability and optimization study
- 2010
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Ingår i: Neurology. - 1526-632X. ; 75:14, s. 1277-1284
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Tidskriftsartikel (refereegranskat)abstract
- Background: Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. Methods: Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. Results: The kappa value for causative classification was 0.80 (95% confidence interval [ CI] 0.78-0.81) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.70 (95% CI 0.69-0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: kappa = 0.81 (95% CI 0.79-0.82) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.79 (95% CI 0.78-0.80) for the 16-subtype CCS. The kappa value for phenotypic classification was 0.79 (95% CI 0.77-0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93-0.98) for cardioembolism, 0.88 (95% CI 0.85-0.91) for small artery occlusion, and 0.79 (0.76-0.82) for other uncommon causes. Conclusions: CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras. Neurology (R) 2010;75:1277-1284
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| 5. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 6. |
- Biffi, Alessandro, et al.
(författare)
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APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study
- 2011
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Ingår i: Lancet Neurology. - 1474-4465. ; 10:8, s. 702-709
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Tidskriftsartikel (refereegranskat)abstract
- Background Carriers of APOE epsilon 2 and epsilon 4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. Methods We investigated the association of APOE epsilon 2 and epsilon 4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE epsilon 4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. Findings For patients with lobar ICH, carriers of the APOE epsilon 2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2. 5x10(-5)), in both replication phases (p=0.008 in Europeans and p=0.016 in African-Americans), and in the meta-analysis (p=3.2x10(-8)). In the meta-analysis, each copy of APOE epsilon 2 increased haematoma size by a mean of 5.3 mL (95% CI 4.7-5.9; p=0.004). Carriers of APOE epsilon 2 had increased mortality (odds ratio [OR] 1.50, 95% CI 1.23-1.82; p=2.45x10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1-52, 1.25-1.85; p=1.74x10(-5)) compared with non-carriers after lobar ICH. APOE epsilon 4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1.08,0.86-1.36; p=0.52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. Interpretation Vasculopathic changes associated with the APOE epsilon 2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the epsilon 2 variant might allow identification of those at increased risk of mortality and poor functional outcomes.
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| 7. |
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| 8. |
- Biffi, Alessandro, et al.
(författare)
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Variants at APOE Influence Risk of Deep and Lobar Intracerebral Hemorrhage
- 2010
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 68:6, s. 934-943
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Prior studies investigating the association between APOE alleles epsilon 2/epsilon 4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for epsilon 2 and epsilon 4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results: Alleles epsilon 2 and epsilon 4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 x 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 x 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele epsilon 4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 x 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation: APOE epsilon 2 and epsilon 4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE epsilon 4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010;68:934-943
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| 9. |
- Dahlberg, Jonas, et al.
(författare)
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Genetic variants in serum and glucocortocoid regulated kinase 1, a regulator of the epithelial sodium channel, are associated with ischaemic stroke.
- 2011
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Ingår i: Journal of Hypertension. - 1473-5598. ; 29, s. 884-889
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Serum and glucocorticoid regulated kinase 1 (SGK1) expression is increased by aldosterone and is a key regulator of the amiloride-sensitive sodium channel (ENaC) in the distal nephron. We have previously shown that two SNPs in SGK1 (rs1057293 and rs1743966) are associated with blood pressure variation and blood pressure progression in the general population. Therefore, we tested the association of these variants with ischaemic stroke. METHODS: Using logistic regression, we analysed rs1057293 and rs1743966 for association with ischaemic stroke in two independent age-matched and sex-matched case-control groups from the twin cities of Lund (cases n = 1837 and controls n = 947) and Malmö (cases n = 888 and controls n = 893) in the Scania region of southern Sweden. RESULTS: In additive models adjusted for hypertension, smoking and diabetes, the major allele (G) of rs1057293 was associated (odds ratio, 95% confidence interval; P value) with ischaemic stroke with similar effect size in both studies; in Lund (1.35, 1.11-1.64; P = 0.002) and Malmö (1.30, 1.03-1.65; P = 0.027). When the two studies were pooled, the overall association was 1.32, 1.14-1.52; P < 0.001. The major allele of rs1743966 (A), which was in linkage disequilibrium with rs1057293, showed a similar trend as rs1057293 G-allele but with slightly weaker effect size and P value. CONCLUSION: In two independent but ethnically similar populations, we observed an association between genetic variants in SGK1 and ischaemic stroke. Interestingly, the association seems to be at least partially independent of blood pressure. This could imply that cerebrovascular ENaC or other SGK1-regulated proteins may be of importance for development of ischaemic stroke.
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| 10. |
- Delavaran, Hossein, et al.
(författare)
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Proximity of brain infarcts to regions of endogenous neurogenesis and involvement of striatum in ischaemic stroke.
- 2012
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Clinical stroke trials with stem cell-based approaches aiming for trophic actions, modulation of inflammation and neuroprotection are ongoing. However, experimental studies also suggest that neuronal replacement by grafted neural stem cells (NSCs) and possibly by endogenous NSCs from the subventricular zone (SVZ) may restore function in the stroke-damaged striatum. To evaluate the potential clinical impact of these findings, we analyzed the spatial relationship of infarcts to the SVZ and the proportion of individuals with striatal lesions in a consecutive series of ischaemic stroke patients. METHODS: Patients aged 20-75 years with first-ever ischaemic stroke underwent DW-MRI of the brain within 4 days after stroke onset. We analyzed location, size, number of acute focal ischaemic abnormalities and their spatial relationship to the SVZ. Stroke severity was assessed using NIH Stroke Scale (NIHSS). RESULTS: Of 108 included patients, the distance from the nearest margin of the infarct(s) to the SVZ was ≤2 mm in 51/102 patients with visible ischaemic lesions on DW-MRI. Twenty-four patients had involvement of striatum. Eight of these had predominantly striatal lesions, that is >50% of the total ischaemic lesion volume was located in caudate nucleus and/or putamen. These 8 patients had a median NIHSS of 3. CONCLUSIONS: Many stroke patients have infarcts located close to the SVZ, providing some supportive evidence that optimized endogenous neurogenesis may have therapeutic potential. However, predominantly striatal infarcts are rare and tend to give mild neurological deficits, indicating that striatum should not be the primary target for neuronal replacement efforts in humans.
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