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| 22. |
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| 23. |
- Carrera, C., et al.
(författare)
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Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 2416-2426
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Tidskriftsartikel (refereegranskat)abstract
- Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 x 10(-5) were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 x 10(-8)) were characterized by in silica functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 x 10(-8); odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 x 10(-8), OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silica studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.
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| 24. |
- Gensicke, H, et al.
(författare)
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Prognostic significance of proteinuria in stroke patients treated with intravenous thrombolysis.
- 2017
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Ingår i: European journal of neurology. - : Wiley. - 1468-1331 .- 1351-5101. ; 24:2, s. 262-269
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Tidskriftsartikel (refereegranskat)abstract
- Proteinuria and estimated glomerular filtration rate (eGFR) are indicators of renal function. Whether proteinuria better predicts outcome than eGFR in stroke patients treated with intravenous thrombolysis (IVT) remains to be determined.In this explorative multicenter IVT register based study, the presence of urine dipstick proteinuria (yes/no), reduced eGFR (<60 ml/min/1.73 m2 ) and the coexistence of both with regard to (i) poor 3-month outcome (modified Rankin Scale score 3-6), (ii) death within 3 months and (iii) symptomatic intracranial hemorrhage (ECASS-II criteria) were compared. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals were calculated.Amongst 3398 patients, 881 (26.1%) had proteinuria and 623 (18.3%) reduced eGFR. Proteinuria [ORadjusted 1.65 (1.37-2.00) and ORadjusted 1.52 (1.24-1.88)] and reduced eGFR [ORadjusted 1.26 (1.01-1.57) and ORadjusted 1.34 (1.06-1.69)] were independently associated with poor functional outcome and death, respectively. After adding both renal markers to the models, proteinuria [ORadjusted+eGFR 1.59 (1.31-1.93)] still predicted poor outcome whilst reduced eGFR [ORadjusted+proteinuria 1.20 (0.96-1.50)] did not. Proteinuria was associated with symptomatic intracranial hemorrhage [ORadjusted 1.54 (1.09-2.17)] but not reduced eGFR [ORadjusted 0.96 (0.63-1.62)]. In 234 (6.9%) patients, proteinuria and reduced eGFR were coexistent. Such patients were at the highest risk of poor outcome [ORadjusted 2.16 (1.54-3.03)] and death [ORadjusted 2.55 (1.69-3.84)].Proteinuria and reduced eGFR were each independently associated with poor outcome and death but the statistically strongest association appeared for proteinuria. Patients with coexistent proteinuria and reduced eGFR were at the highest risk of poor outcome and death.
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| 25. |
- Liebkind, R., et al.
(författare)
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Diabetes and intracerebral hemorrhage: baseline characteristics and mortality
- 2018
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101. ; 25:6, s. 825-832
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Tidskriftsartikel (refereegranskat)abstract
- Background and purposeAcknowledging the conflicting evidence for diabetes as a predictor of short- and long-term mortality following an intracerebral hemorrhage (ICH), we compared baseline characteristics and 30-day and long-term mortality between patients with and without diabetes after an ICH, paying special attention to differences between type 1 (T1D) and type 2 (T2D) diabetes. MethodsPatients with a first-ever ICH were followed for a median of 2.3years. Adjusting for demographics, comorbidities and documented ICH characteristics increasing mortality after ICH, logistic regression analysis assessed factors associated with case fatality and 1-year survival among the 30-day survivors. Diabetes was compared with patients without diabetes in separate models as (i) any diabetes and (ii) T1D or T2D. ResultsOf our 969 patients, 813 (83.9%) had no diabetes, 41 (4.2%) had T1D and 115 (11.9%) had T2D. Compared with patients without diabetes, those with diabetes were younger, more often men and more frequently had hypertension, coronary heart disease and chronic kidney disease, with similar ICH characteristics. Patients with T1D were younger, more often had chronic kidney disease and brainstem ICH, and less often had atrial fibrillation and lobar ICH, than did patients with T2D. Diabetes had no impact on case fatality. Any diabetes (odds ratio, 2.57; 1.19-5.52), T1D (odds ratio, 7.04; 1.14-43.48) and T2D (odds ratio, 2.32; 1.04-5.17) were independently associated with 1-year mortality. ConclusionsPatients with ICH with diabetes exhibited a distinct pattern of comorbidities and disease characteristics with specific differences between T1D and T2D. Despite their younger age, T1D seems to carry a substantially higher likelihood of long-term mortality after an ICH than does T2D.
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| 26. |
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| 27. |
- Rannikmäe, K., et al.
(författare)
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Reliability of intracerebral hemorrhage classification systems: A systematic review
- 2016
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 11:6, s. 626-636
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accurately distinguishing non-traumatic intracerebral hemorrhage (ICH) subtypes is important since they may have different risk factors, causal pathways, management, and prognosis. We systematically assessed the inter- and intra-rater reliability of ICH classification systems. Methods: We sought all available reliability assessments of anatomical and mechanistic ICH classification systems from electronic databases and personal contacts until October 2014. We assessed included studies’ characteristics, reporting quality and potential for bias; summarized reliability with kappa value forest plots; and performed meta-analyses of the proportion of cases classified into each subtype. Summary of review: We included 8 of 2152 studies identified. Inter- and intra-rater reliabilities were substantial to perfect for anatomical and mechanistic systems (inter-rater kappa values: anatomical 0.78–0.97 [six studies, 518 cases], mechanistic 0.89–0.93 [three studies, 510 cases]; intra-rater kappas: anatomical 0.80–1 [three studies, 137 cases], mechanistic 0.92–0.93 [two studies, 368 cases]). Reporting quality varied but no study fulfilled all criteria and none was free from potential bias. All reliability studies were performed with experienced raters in specialist centers. Proportions of ICH subtypes were largely consistent with previous reports suggesting that included studies are appropriately representative. Conclusions: Reliability of existing classification systems appears excellent but is unknown outside specialist centers with experienced raters. Future reliability comparisons should be facilitated by studies following recently published reporting guidelines. © 2016, © 2016 World Stroke Organization.
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| 30. |
- Traylor, Matthew, et al.
(författare)
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Genetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studies
- 2021
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Ingår i: The Lancet Neurology. - 1474-4422. ; 20:5, s. 351-361
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Tidskriftsartikel (refereegranskat)abstract
- Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. Funding: British Heart Foundation.
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