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Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage.

ABSTRACT: BACKGROUND:Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E (APOE) genotype influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE epsilon4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans. OBJECTIVE AND METHODS:To comprehensively search, identify, assess and carry out meta-analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke, intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH). RESULTS:Main analyses included data from nine studies on 2262 patients (1453 with ischaemic stroke, 199 with ICH and 610 with SAH). Overall, epsilon4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. Epsilon4+ genotypes were associated with increased death or dependency after SAH (relative risk (RR) 1.40, 95% confidence interval (CI) 1.06 to 1.84), with a trend towards a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not with ischaemic stroke (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone. CONCLUSIONS:APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.

SUBMITTER: Martinez-Gonzalez NA

PROVIDER: S-EPMC2077401 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage.

Martínez-González N A NA Sudlow C L M CL

Journal of neurology, neurosurgery, and psychiatry 20060822 12

<h4>Background</h4>Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E (APOE) genotype influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE epsilon4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.<h4>Objective and methods</h4>To comprehensively search, identify, assess and carry out meta-analyses of studies reporting on th ...[more]

PMID: 16926234

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Project description:Aim: Since tissue inhibitors of matrix metalloproteinase 3 (TIMP-3) was reported to be a potential risk factor of atherosclerosis, aneurysm, hypertension, and post-ischaemic neuronal injury, it may also be a candidate risk factor of stress. Therefore, this study was designed to explore the causal role of TIMP-3 in the risk of ischaemic stroke (IS) and intracerebral haemorrhage (ICH), which are the two main causes of stress via this Mendelian Randomisation (MR) study. Methods: The summarised data of TIMP-3 level in circulation was acquired from the Cooperative Health Research in the Region of Augsburg public database and the outcome of IS and ICH was obtained from genome-wide association studies conducted by MEGASTROKE and the International Stroke Genetics Consortium, respectively. Five statistical methods including inverse-variance weighting, weighted-median analysis, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test, and MR-Robust Adjusted Profile Score were applied to evaluate the causal role of TIMP-3 in the occurrence of IS and ICH. Inverse-variance weighting was applied for assessing causality. Furthermore, heterogeneity and pleiotropic tests were utilised to confirm the reliability of this study. Results: We found that TIMP-3 could be a positively causal relationship with the incidence of IS (OR = 1.026, 95% CI: 1.007-1.046, p = 0.0067), especially for the occurrence of small vessel stroke (SVS; OR = 1.045, 95% CI: 1.016-1.076, p = 0.0024). However, the causal effects of TIMP-3 on another IS subtype cardioembolic stroke (CES; OR = 1.049, 95% CI: 1.006-1.094, p = 0.024), large artery stroke (LAS; OR = 1.0027, 95% CI: 0.9755-1.0306, p = 0.849) and ICH (OR = 0.9900, 95% CI: 0.9403-1.0423, p = 0.701), as well as ICH subtypes were not observed after Bonferroni corrections (p = 0.00714). Conclusion: Our results revealed that high levels of circulating TIMP-3 causally increased the risk of developing IS and SVS, but not CES, LAS, ICH, and all ICH subtypes. Further investigation is required to elucidate the underlying mechanism.

Project description:BackgroundIt is often assumed that blood pressure increases acutely after major stroke, resulting in so-called post-stroke hypertension. In view of evidence that the risks and benefits of blood pressure-lowering treatment in acute stroke might differ between patients with major ischaemic stroke and those with primary intracerebral haemorrhage, we compared acute-phase and premorbid blood pressure levels in these two disorders.MethodsIn a population-based study in Oxfordshire, UK, we recruited all patients presenting with stroke between April 1, 2002, and March 31, 2012. We compared all acute-phase post-event blood pressure readings with premorbid readings from 10-year primary care records in all patients with acute major ischaemic stroke (National Institutes of Health Stroke Scale >3) versus those with acute intracerebral haemorrhage.FindingsOf 653 consecutive eligible patients, premorbid and acute-phase blood pressure readings were available for 636 (97%) individuals. Premorbid blood pressure (total readings 13,244) had been measured on a median of 17 separate occasions per patient (IQR 8-31). In patients with ischaemic stroke, the first acute-phase systolic blood pressure was much lower than after intracerebral haemorrhage (158·5 mm Hg [SD 30·1] vs 189·8 mm Hg [38·5], p<0·0001; for patients not on antihypertensive treatment 159·2 mm Hg [27·8] vs 193·4 mm Hg [37·4], p<0·0001), was little higher than premorbid levels (increase of 10·6 mm Hg vs 10-year mean premorbid level), and decreased only slightly during the first 24 h (mean decrease from <90 min to 24 h 13·6 mm Hg). By contrast with findings in ischaemic stroke, the mean first systolic blood pressure after intracerebral haemorrhage was substantially higher than premorbid levels (mean increase of 40·7 mm Hg, p<0·0001) and fell substantially in the first 24 h (mean decrease of 41·1 mm Hg; p=0·0007 for difference from decrease in ischaemic stroke). Mean systolic blood pressure also increased steeply in the days and weeks before intracerebral haemorrhage (regression p<0·0001) but not before ischaemic stroke. Consequently, the first acute-phase blood pressure reading after primary intracerebral haemorrhage was more likely than after ischaemic stroke to be the highest ever recorded (OR 3·4, 95% CI 2·3-5·2, p<0·0001). In patients with intracerebral haemorrhage seen within 90 min, the highest systolic blood pressure within 3 h of onset was 50 mm Hg higher, on average, than the maximum premorbid level whereas that after ischaemic stroke was 5·2 mm Hg lower (p<0·0001).InterpretationOur findings suggest that systolic blood pressure is substantially raised compared with usual premorbid levels after intracerebral haemorrhage, whereas acute-phase systolic blood pressure after major ischaemic stroke is much closer to the accustomed long-term premorbid level, providing a potential explanation for why the risks and benefits of lowering blood pressure acutely after stroke might be expected to differ.FundingWellcome Trust, Wolfson Foundation, UK Medical Research Council, Stroke Association, British Heart Foundation, National Institute for Health Research.

Project description:BACKGROUND:Carriers of APOE ?2 and ?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 ?2 and ?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 ?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 ?2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10(-5)), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10(-8)). In the meta-analysis, each copy of APOE ?2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE ?2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10(-5)) compared with non-carriers after lobar ICH. APOE ?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 ?2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the ?2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. FUNDING:US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.

Dataset Information

Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage.

Publications

Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage.

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