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1.  Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies 
Traylor, Matthew | Farrall, Martin | Holliday, Elizabeth G | Sudlow, Cathie | Hopewell, Jemma C | Cheng, Yu-Ching | Fornage, Myriam | Ikram, M Arfan | Malik, Rainer | Bevan, Steve | Thorsteinsdottir, Unnur | Nalls, Mike A | Longstreth, WT | Wiggins, Kerri L | Yadav, Sunaina | Parati, Eugenio A | DeStefano, Anita L | Worrall, Bradford B | Kittner, Steven J | Khan, Muhammad Saleem | Reiner, Alex P | Helgadottir, Anna | Achterberg, Sefanja | Fernandez-Cadenas, Israel | Abboud, Sherine | Schmidt, Reinhold | Walters, Matthew | Chen, Wei-Min | Ringelstein, E Bernd | O'Donnell, Martin | Ho, Weang Kee | Pera, Joanna | Lemmens, Robin | Norrving, Bo | Higgins, Peter | Benn, Marianne | Sale, Michele | Kuhlenbäumer, Gregor | Doney, Alexander S F | Vicente, Astrid M | Delavaran, Hossein | Algra, Ale | Davies, Gail | Oliveira, Sofia A | Palmer, Colin N A | Deary, Ian | Schmidt, Helena | Pandolfo, Massimo | Montaner, Joan | Carty, Cara | de Bakker, Paul I W | Kostulas, Konstantinos | Ferro, Jose M | van Zuydam, Natalie R | Valdimarsson, Einar | Nordestgaard, Børge G | Lindgren, Arne | Thijs, Vincent | Slowik, Agnieszka | Saleheen, Danish | Paré, Guillaume | Berger, Klaus | Thorleifsson, Gudmar | Hofman, Albert | Mosley, Thomas H | Mitchell, Braxton D | Furie, Karen | Clarke, Robert | Levi, Christopher | Seshadri, Sudha | Gschwendtner, Andreas | Boncoraglio, Giorgio B | Sharma, Pankaj | Bis, Joshua C | Gretarsdottir, Solveig | Psaty, Bruce M | Rothwell, Peter M | Rosand, Jonathan | Meschia, James F | Stefansson, Kari | Dichgans, Martin | Markus, Hugh S
Lancet Neurology  2012;11(11):951-962.
Summary
Background
Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.
Methods
We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.
Findings
We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort.
Interpretation
Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.
Funding
Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).
doi:10.1016/S1474-4422(12)70234-X
PMCID: PMC3490334  PMID: 23041239
2.  Genetic Susceptibility for Ischemic Infarction and Arteriolosclerosis based on Neuropathologic Evaluations 
Cerebrovascular diseases (Basel, Switzerland)  2013;36(3):10.1159/000352054.
Background
Recent genetic studies of stroke and related risk factors have identified a growing number of susceptibility loci; however, the relationship of these alleles to ischemic stroke is unknown. The challenge in finding reproducible loci of ischemic stroke susceptibility may be in part related to the etiologic heterogeneity in clinically-defined stroke subtypes. In this study, we tested whether known single nucleotide polymorphisms (SNPs) associated with stroke or putative stroke risk factors are associated with neuropathologically-defined micro- or macroscopic infarcts and with arteriolosclerosis.
Methods
Measures of neuropathology and genotyping were available from 755 deceased participants from the Religious Orders Study and the Rush Memory and Aging Project. All donated brains were examined by a board-certified neuropathologist using standardized protocol for the presence of microscopic infarct, macroscopic infarct, and artereiolosclerosis (lipohylinosis). In primary analysis, 74 candidate SNPs previously associated (p < 5×10−8) with ischemic stroke or known risk factors, including atrial fibrillation (AF), hypertension, diabetes, low density lipoprotein (LDL) level, and carotid artery stenosis, were evaluated for association with neuropathological endpoints. We performed secondary exploratory analysis to include additional 93 SNPs associated with putative ischemic stroke risk factors including SNPS associated with high density lipoprotein (HDL), triglyceride serum levels, myocardial infarction, coronary artery disease, and cerebral white matter disease. Regression models relating SNPs to cerebrovascular neuropathology were adjusted for age at death, gender, and cohort membership.
Results
The strongest associations seen for both macroscopic and microscopic infarcts were risk variants associated with diabetes. The diabetes risk variant rs7578326 located near the IRS1 locus was associated with both macroscopic (OR=0.73, p=0.011) and microscopic (OR=0.71, p=0.009) infarct pathology. Another diabetes susceptibility locus rs12779790 located between the calcium/calmodulin-dependent protein kinase ID (CAMK1D) and cell division cycle 123 homolog (CDC123) genes is also associated with both macroscopic (OR=1.40, p=0.0292) and microscopic infarcts (OR=1.43, p=0.0285). Diabetes risk allele, rs864745, within JAZF1, was associated with arteriolosclerosis (OR=0.80, p=0.014). We observed suggestive associations with the diabetes risk alleles rs7961581 (p=0.038; between TSPAN8 and LGR5) and rs5215 (p=0.043; KCNJ11), the LDL risk variant rs11206510 (p=0.045; PCSK9), as well as the AF risk locus ZFHX3. The CDKN2A/B locus (rs2383207, 9p21), identified initially as a susceptibility allele for myocardial infarction and recently implicated in large vessel stroke, was associated with macroscopic infarct pathology in our autopsy cohort (OR=1.26, p=0.031).
Conclusion
Our results suggest replication of the candidate CDKN2A/B stroke susceptibility locus with directly measured macroscopic stroke neuropathology, and further implicate several diabetes and other risk alleles with secondary, pleiotropic associations to stroke-related pathology in our autopsy cohort. When coupled with larger sample sizes, cerebrovascular neuropathologic phenotypes will likely be powerful tools for the genetic dissection of susceptibility for ischemic stroke.
doi:10.1159/000352054
PMCID: PMC3871868  PMID: 24135527
ischemic stroke etiology; pathology; genetic risk factors of stroke; genetics of vascular pathology and stroke; diabetes mellitus; arteriolosclerosis
3.  Genetics of Ischaemic Stroke among Persons of Non-European Descent: A Meta-Analysis of Eight Genes Involving ∼ 32,500 Individuals 
PLoS Medicine  2007;4(4):e131.
Background
Ischaemic stroke in persons of European descent has a genetic basis, but whether the stroke-susceptibility alleles, the strength of any association, and the extent of their attributable risks are the same in persons of non-European descent remains unanswered. Whether ethnicity itself has a relevant or substantial contribution on those effect estimates is controversial. Comparative analyses between the ethnic groups may allow general conclusions to be drawn about polygenic disorders.
Methods and Findings
We performed a literature-based systematic review of genetic association studies in stroke in persons of non-European descent. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined for each gene–disease association using fixed and random effect models. We further performed a comparative genetic analysis across the different ethnic groups (including persons of European descent derived from our previous meta-analysis) to determine if genetic risks varied by ethnicity. Following a review of 500 manuscripts, eight candidate gene variants were analysed among 32,431 individuals (12,883 cases and 19,548 controls), comprising mainly Chinese, Japanese, and Korean individuals. Of the eight candidate genes studied, three were associated with ischaemic stroke: the angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism with a mean OR of 1.90 (95% CI 1.23–2.93) in the Chinese and 1.74 (95% CI 0.88–3.42) in the Japanese; the summary OR for the C677T variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) was 1.18 (95% CI 0.90–1.56) in Chinese and 1.34 (95% CI 0.87–2.06) in Koreans; and the pooled OR for the apolipoprotein E (APOE) gene was 2.18 (95% CI 1.52–3.13) in Chinese and 1.51 (95% CI 0.93–2.45) in Japanese. Comparing the commonly investigated stroke genes among the Asian groups against studies in persons of European descent, we found an absence of any substantial qualitative or quantitative interaction for ORs by ethnicity. However, the number of individuals recruited per study in the studies of persons of non-European descent was significantly smaller compared to studies of persons of European descent, despite a similar number of studies conducted per gene.
Conclusions
These data suggest that genetic associations studied to date for ischaemic stroke among persons of non-European descent are similar to those for persons of European descent. Claims of differences in genetic effects among different ethnic populations for complex disorders such as stroke may be overstated. However, due to the limited number of gene variants evaluated, the relatively smaller number of individuals included in the meta-analyses of persons of non-European descent in stroke, and the possibility of publication bias, the existence of allele variants with differential effects by ethnicity cannot be excluded.
This meta-analysis found that genetic associations so far studied for ischemic stroke among non-Europeans are similar to those found for persons of European descent.
Editors' Summary
Background.
A stroke occurs when the blood supply to part of the brain is interrupted, either because a blood vessel supplying the brain becomes blocked or because one ruptures. Strokes are a substantial cause of death and disability worldwide, with most of the burden affecting people living in developed countries. Most strokes fall into a category termed ischemic stroke. This type is caused by blockages in the blood vessels supplying the brain, which can happen when there is a buildup of fatty deposits or clots within the blood vessels. Many of the risk factors for this particular type of stroke are affected by an individual's behavior, including for example smoking, high blood pressure, diabetes, inactivity, and so on. In addition, variations in an individual's genetic makeup might affect his or her chance of having a stroke. Previous research studies have shown that variants in many different genes are likely to be involved in determining the overall risk of having a stroke, each variant contributing in a small way to the risk.
Why Was This Study Done?
The group performing this study had previously carried out a systematic review of existing research, looking specifically at the genetics of ischemic stroke among people of European origin (often called “Caucasians”). However, it was not obvious whether the genetic risk factors for stroke they found would be the same for people from a different ethnic background. Therefore the research group wanted to find out what the genetic risk factors were for stroke among people of non-European origin and to compare these findings with those of their previous systematic review. This research might help to find out whether the genetic risk factors for stroke were different in people from different parts of the world.
What Did the Researchers Do and Find?
As a starting point, these researchers wanted to find all the different studies that had already been carried out examining the effect of genetic risk factors on stroke among people of non-European origin. To do this, searches were carried out of electronic databases using a particular set of terms. All resulting studies that involved genetic research in people of non-European origin and in which strokes were confirmed by brain scanning were then evaluated in more detail. The findings of different studies were combined if at least three studies were available for the same genetic variant. Eventually 60 studies were found that looked at the association between eight specific gene variants and stroke. The only data that could be included in a combined analysis came from Chinese, Japanese, and Korean populations. Three of the eight gene variants were associated with an increased risk of stroke. Those three gene variants were ACE I/D (a variant in the gene coding for angiotensin 1-converting enzyme, which is involved in controlling blood pressure); a variant in MTHFR (which codes for the enzyme methylenetetrahydrofolate reductase, and which converts certain amino acids within cells); and a variant in the gene APOE, which codes for a protein that plays a role in breaking down fats. The researchers then compared their findings from this study with the findings of a previous systematic review they had carried out among people of European origin. Overall, each gene studied seemed to have a similar effect in the different populations, with the exception of APOE, which seemed to be associated with stroke in the Asian studies but not in the studies from people of non-European origin. The researchers also found that generally the Asian studies suggested a slightly greater effect of each gene variant than the studies in people of non-European origin did.
What Do These Findings Mean?
These findings suggest that, with the possible exception of APOE, similar gene variants play a role in determining stroke risk in people of European origin and Asian populations. Although generally the studies examined here suggested a slightly greater effect of these gene variants in Asian populations, this is not necessarily a real finding. This greater effect may just be due to small-study bias. Small-study bias describes the observation that small research studies are more likely to produce a false positive result than are large research studies. Therefore, future studies that examine the genetic basis of stroke should recruit much larger numbers of participants from populations made up of people of non-European origin than has previously been the case.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040131.
Health Encyclopedia entry on stroke from NHS Direct (UK National Health Service patient information)
Stroke Information page from the National Institute of Neurological Disorders and Stroke (provided by the US National Institutes of Health)
The Stroke Association, a UK charity funding this study
Information from the World Health Organization on the distribution and burden of stroke worldwide
The WHO has a world atlas of heart disease and stroke
doi:10.1371/journal.pmed.0040131
PMCID: PMC1876409  PMID: 17455988
4.  Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke 
Nature genetics  2012;44(3):328-333.
Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9 (HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes.
doi:10.1038/ng.1081
PMCID: PMC3303115  PMID: 22306652
5.  Modifiable Etiological Factors and the Burden of Stroke from the Rotterdam Study: A Population-Based Cohort Study 
PLoS Medicine  2014;11(4):e1001634.
Using data from the Rotterdam study, Michiel Bos and colleagues estimate the proportion of strokes that are attributable to established modifiable etiological factors for stroke.
Please see later in the article for the Editors' Summary
Background
Stroke prevention requires effective treatment of its causes. Many etiological factors for stroke have been identified, but the potential gain of effective intervention on these factors in terms of numbers of actually prevented strokes remains unclear because of the lack of data from cohort studies. We assessed the impact of currently known potentially modifiable etiological factors on the occurrence of stroke.
Methods and Findings
This population-based cohort study was based on 6,844 participants of the Rotterdam Study who were aged ≥55 y and free from stroke at baseline (1990–1993). We computed population attributable risks (PARs) for individual risk factors and for risk factors in combination to estimate the proportion of strokes that could theoretically be prevented by the elimination of etiological factors from the population.
The mean age at baseline was 69.4 y (standard deviation 6.3 y). During follow-up (mean follow-up 12.9 y, standard deviation 6.3 y), 1,020 strokes occurred. The age- and sex-adjusted combined PAR of prehypertension/hypertension, smoking, diabetes mellitus, atrial fibrillation, coronary disease, and overweight/obesity was 0.51 (95% CI 0.41–0.62) for any stroke; hypertension and smoking were the most important etiological factors. C-reactive protein, fruit and vegetable consumption, and carotid intima-media thickness in combination raised the total PAR by 0.06. The PAR was 0.55 (95% CI 0.41–0.68) for ischemic stroke and 0.70 (95% CI 0.45–0.87) for hemorrhagic stroke.
The main limitations of our study are that our study population comprises almost exclusively Caucasians who live in a middle and high income area, and that risk factor awareness is higher in a study cohort than in the general population.
Conclusions
About half of all strokes are attributable to established causal and modifiable factors. This finding encourages not only intervention on established etiological factors, but also further study of less well established factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people worldwide have a stroke. About 6 million of these people die within hours, and another 5 million are left disabled. Stroke occurs when the brain's blood supply is suddenly interrupted by a blood vessel in the brain being blocked by a blood clot (ischemic stroke) or bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. In the longer term, post-stroke rehabilitation can help overcome the disabilities caused by stroke, and various drugs alongside behavioral counselling can reduce the risk of a second stroke.
Why Was This Study Done?
Fifty years ago, it was discovered that treatment of high blood pressure (hypertension) reduces the risk of stroke among people with severe hypertension. This discovery led researchers to search for other potentially modifiable etiological factors for stroke (risk factors that cause stroke). The list of established etiological factors now includes smoking, diabetes, atrial fibrillation (an irregular heartbeat), heart disease, and overweight/obesity, in addition to hypertension. But how many strokes would modification of these causal risk factors prevent? In this population-based cohort study, the researchers calculate the individual and combined population attributable risks (PARs) for these established etiological factors to provide an estimate of what proportion of strokes could theoretically be prevented by optimal treatment of known etiological factors. A population-based cohort study enrolls a group of people, determines their characteristics at baseline, and follows them to see whether specific characteristics are associated with specific outcomes. A PAR of an etiological factor for a disease indicates the proportion of that disease in the population that would not occur in the absence of the risk factor.
What Did the Researchers Do and Find?
The researchers used data from 6,844 participants in the Rotterdam Study, which was designed to investigate the causes and consequences of long-term and disabling diseases in the elderly. At baseline, all of the participants were over 55 years old and free from stroke. During follow-up, 1,020 strokes occurred among the participants. Using data on exposure at baseline to various etiological factors for stroke, the researchers calculated PARs for individual factors and used a special statistical technique to calculate PARs for the factors in combination. The combined PAR of prehypertension/hypertension, smoking, diabetes, atrial fibrillation, heart disease, and overweight/obesity was 0.51 for any stroke. That is, about half of the strokes in the study population were attributable to this combination of etiological factors. Hypertension and smoking were the most important individual factors (PARs of 0.36 and 0.16, respectively). Notably, the inclusion of several less well established etiological factors (increased blood levels of C-reactive protein, low fruit and vegetable consumption, and thickening of the lining of arteries) only raised the total PAR for any stroke by 0.06.
What Do These Findings Mean?
These findings indicate that about half of the strokes in the study cohort were attributable to established modifiable etiological factors and could theoretically be prevented by eliminating these risk factors from the population. Previous studies have estimated that a larger proportion of strokes could be prevented by eliminating known etiological factors. The researchers acknowledge that some aspects of their study may have led to an underestimation of the proportion of stroke attributable to established etiological factors and note that their findings may not be generalizable to underprivileged or racially diverse populations. Nevertheless, they argue that previous studies are likely to have overestimated the PARs for stroke because they were based on case–control studies (in which exposure to etiological factors was assessed after a stroke had occurred in cases and control individuals, rather than before a stroke as in a population-based cohort study) and often did not use optimal statistical techniques to calculate the total PAR. Importantly, these new findings underscore the importance of interventions targeted at reducing smoking and hypertension and support the search for additional etiological factors for stroke.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001634.
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation including personal stories (in English and Spanish); the US National Institutes of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices website also provides information about stroke for patients and their families, including personal stories
MedlinePlus has links to additional resources about stroke (in English and Spanish)
Information about the Rotterdam Study is available
The UK not-for-profit website Healthtalkonline provides personal stories about stroke
doi:10.1371/journal.pmed.1001634
PMCID: PMC4004543  PMID: 24781247
6.  A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach 
PLoS Genetics  2014;10(7):e1004469.
Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10−7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05–1.32); meta-analysis p = 2.6×10−8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10−15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
Author Summary
Ischaemic stroke places an enormous burden on global healthcare. However, the disease processes that lead to stroke are not fully understood. Genome-wide association studies have recently established that common genetic variants can increase risk of ischaemic stroke and its subtypes. In this study, we aimed to identify novel genetic associations with ischaemic stroke and its subtypes by addressing the fact that younger onset cases may have a stronger genetic component, and using this information in our analyses. We identify a novel genetic variant on chromosome 11 (rs660599), which is associated with increased risk of large artery stroke. We also show that mRNA expression of the nearest gene (MMP12) is higher in arteries with the disease process underlying large artery stroke (atherosclerosis). Finally, we evaluate our novel analysis approach, and show that our method is likely to identify further associations with ischaemic stroke.
doi:10.1371/journal.pgen.1004469
PMCID: PMC4117446  PMID: 25078452
7.  Stroke: secondary prevention  
Clinical Evidence  2010;2010:0207.
Introduction
People with a history of stroke or transient ischaemic attack (TIA) are at high risk of all vascular events, such as myocardial infarction (MI), but are at particular risk of subsequent stroke (about 10% in the first year and about 5% each year thereafter).
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive non-surgical interventions in people with previous stroke or transient ischaemic attack? What are the effects of preventive surgical interventions in people with previous stroke or transient ischaemic attack? What are the effects of preventive anticoagulant and antiplatelet treatments in people with atrial fibrillation and previous stroke or transient ischaemic attack? What are the effects of preventive anticoagulant and antiplatelet treatments in people with atrial fibrillation and without previous stroke or transient ischaemic attack? What are the effects of preventive anticoagulant and antiplatelet treatments in people with atrial fibrillation and without previous stroke or transient ischaemic attack and with low to moderate risk of stroke or transient ischaemic attack? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 130 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alternative antiplatelet regimens to aspirin, anticoagulation (oral dosing, or in those with sinus rhythm), aspirin (high or low dose), blood pressure reduction, carotid and vertebral percutaneous transluminal angioplasty (PTA), carotid endarterectomy (in people with: asymptomatic but severe carotid artery stenosis, less than 0% symptomatic carotid artery stenosis, moderate [30%-49%] symptomatic carotid artery stenosis, moderately severe [50%-69%] symptomatic carotid artery stenosis, severe [greater than 70%] symptomatic carotid artery stenosis, or symptomatic near occlusion of the carotid artery), cholesterol reduction, vitamin B supplements (including folate), and different regimens to lower blood pressure.
Key Points
Prevention in this context is the long-term management of people with previous stroke or TIA, and of people at high risk of stroke for other reasons, such as atrial fibrillation. Risk factors for stroke include: previous stroke or TIA; increasing age; hypertension; diabetes; cigarette smoking; and emboli associated with atrial fibrillation, artificial heart valves, or MI.
Antiplatelet treatment effectively reduces the risk of stroke in people with previous stroke or TIA. High-dose aspirin (500-1500 mg/day) seems as equally effective as low-dose aspirin (75-150 mg/day), although it may increase GI adverse effects. Adding dipyridamole to aspirin is beneficial in reducing composite vascular end points and stroke compared with aspirin alone. Risk reduction appears greater with extended-release compared with immediate-release dipyridamole.The net risk of recurrent stroke or major haemorrhagic event is similar with clopidogrel and aspirin plus dipyridamole.
Treatments to reduce blood pressure are effective for reducing the risk of serious vascular events in people with previous stroke or TIA. Blood pressure reduction seems beneficial irrespective of the type of qualifying cerebrovascular event (ischaemic or haemorrhagic), or even whether people are hypertensive.Aggressive blood pressure lowering should not be considered in people with acute stenosis of the carotid or vertebral arteries, because of the risk of precipitating a stroke.
Carotid endarterectomy effectively reduces the risk of stroke in people with greater than 50% carotid stenosis, is not effective in people with 30% to 49% carotid stenosis, and increases the risk of stroke in people with less than 30% stenosis. However, it does not seem beneficial in people with near occlusion.
Cholesterol reduction using statins seems to reduce the risk of stroke irrespective of baseline cholesterol or coronary artery disease (CAD). Non-statin cholesterol reduction does not seem to reduce the risk of stroke.
We found insufficient evidence to judge the efficacy of carotid percutaneous transluminal angioplasty, carotid percutaneous transluminal angioplasty plus stenting, or vertebral percutaneous transluminal angioplasty in people with recent carotid or vertebral TIA or stenosis.
Vitamin B supplements (including folate) do not seem beneficial in reducing mortality or the risk of stroke.
Anticoagulation does not seem beneficial in reducing stroke in people with previous ischaemic stroke and normal sinus rhythm, but does increase the risk of intra- and extracranial haemorrhage. This is especially true for patients with TIAs or minor ischaemic stroke as the qualifying event.
In people with atrial fibrillation, oral anticoagulants reduce the risk of stroke in people with previous stroke or TIA, and in people with no previous stroke or TIA who are at high risk of stroke or TIA, but we don't know whether they are effective in people with no previous stroke or TIA who are at low risk of stroke or TIA. In people with atrial fibrillation, we don't know whether aspirin reduces the risk of stroke in people with previous stroke or TIA, or in people without previous stroke or TIA who are at low risk of stroke or TIA, but they may be unlikely to be effective in people without previous stroke or TIA who are at high risk of stroke or TIA.
PMCID: PMC2907594
8.  Stroke Genetics: A Review and Update 
Journal of Stroke  2014;16(3):114-123.
Stroke genetics includes several topics of clinical interest, including (1) molecular genetic variations affecting risk of monogenic stroke syndromes; (2) molecular genetic variations affecting risk of common stroke syndromes, sometimes with specific effects on risk of specific main types of stroke or subtypes of ischemic and hemorrhagic stroke; (3) genetics of conditions associated with stroke risk e.g. white matter hyperintensities, atrial fibrillation and hypertension; (4) hereditary causes of familial aggregation of stroke; (5) epigenetic impact on protein expression during acute brain injury; (6) genetic influence on stroke recovery; and (7) pharmacogenetics. Genetic research methods include candidate gene studies; Genome Wide Association Studies; family studies; RNA and protein analyses; and advanced computer-aided analytical methods to detect statistically significant associations. Several methods that could improve our knowledge of stroke genetics are being developed e.g.: Exome content analysis; Next-generation sequencing; Whole genome sequencing; and Epigenetics. During 2012-2014, several Single Nucleotide Polymorphisms (SNPs) have been related to common ischemic stroke risk. Certain SNPs have been associated with risk of specific ischemic stroke subtypes such as large vessel disease and cardiac embolism, particular subtypes of intracerebral hemorrhage (ICH), especially lobar ICH, and with prognosis after ICH. Large international studies on stroke recovery and exome content are ongoing. Advanced mathematical models have been used to study how several SNPs can act together and increase stroke risk burden. Such efforts require large numbers of patients and controls, which is achieved by co-operation in large international consortia such as the International Stroke Genetics Consortium. This overview includes an introduction to genetics, stroke genetics in general, and different genetic variations that may influence stroke risk. It presents some of the latest reports on stroke genetics published in high impact journals. The role of pharmacogenetics, the current clinical situation, and future prospects will also be discussed.
doi:10.5853/jos.2014.16.3.114
PMCID: PMC4200595  PMID: 25328870
Stroke; Genetics; Pharmacogenetics; Genetic Association Studies; Humans
9.  Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression 
PLoS Genetics  2010;6(4):e1000899.
Single nucleotide polymorphisms (SNPs) on chromosome 9p21 are associated with coronary artery disease, diabetes, and multiple cancers. Risk SNPs are mainly non-coding, suggesting that they influence expression and may act in cis. We examined the association between 56 SNPs in this region and peripheral blood expression of the three nearest genes CDKN2A, CDKN2B, and ANRIL using total and allelic expression in two populations of healthy volunteers: 177 British Caucasians and 310 mixed-ancestry South Africans. Total expression of the three genes was correlated (P<0.05), suggesting that they are co-regulated. SNP associations mapped by allelic and total expression were similar (r = 0.97, P = 4.8×10−99), but the power to detect effects was greater for allelic expression. The proportion of expression variance attributable to cis-acting effects was 8% for CDKN2A, 5% for CDKN2B, and 20% for ANRIL. SNP associations were similar in the two populations (r = 0.94, P = 10−72). Multiple SNPs were independently associated with expression of each gene (P<0.05 after correction for multiple testing), suggesting that several sites may modulate disease susceptibility. Individual SNPs correlated with changes in expression up to 1.4-fold for CDKN2A, 1.3-fold for CDKN2B, and 2-fold for ANRIL. Risk SNPs for coronary disease, stroke, diabetes, melanoma, and glioma were all associated with allelic expression of ANRIL (all P<0.05 after correction for multiple testing), while association with the other two genes was only detectable for some risk SNPs. SNPs had an inverse effect on ANRIL and CDKN2B expression, supporting a role of antisense transcription in CDKN2B regulation. Our study suggests that modulation of ANRIL expression mediates susceptibility to several important human diseases.
Author Summary
Genetic variants on chromosome 9p21 have been associated with several important diseases including coronary artery disease, diabetes, and multiple cancers. Most of the risk variants in this region do not alter any protein sequence and are therefore likely to act by influencing the expression of nearby genes. We investigated whether chromosome 9p21 variants are correlated with expression of the three nearest genes (CDKN2A, CDKN2B, and ANRIL) which might mediate the association with disease. Using two different techniques to study effects on expression in blood from two separate populations of healthy volunteers, we show that variants associated with disease are all correlated with ANRIL expression, but associations with the other two genes are weaker and less consistent. Multiple genetic variants are independently associated with expression of all three genes. Although total expression levels of CDKN2A, CDKN2B, and ANRIL are positively correlated, individual genetic variants influence ANRIL and CDKN2B expression in opposite directions, suggesting a possible role of ANRIL in CDKN2B regulation. Our study suggests that modulation of ANRIL expression mediates susceptibility to several important human diseases.
doi:10.1371/journal.pgen.1000899
PMCID: PMC2851566  PMID: 20386740
10.  Ischaemic stroke is associated with the ABO locus: the Euroclot study 
Annals of neurology  2013;73(1):16-31.
Objectives
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischaemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Methods
Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n=2,100 Stage 1) were examined in ischemic stroke (n=4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases 55,000 controls) was used for replication (Stage 3).
Results
Stage 1 identified 524 SNPs from 23 LD blocks having significant association (p<5 ×10-8) with one or more coagulation/fibrin phenotypes. Most striking associations included SNP rs5985 with factor XIII activity (p=2.6×10-186), rs10665 with FVII (p = 2.4×10-47) and rs505922 in the ABO gene with both von Willebrand Factor (vWF p=4.7×10-57) and factor VIII (p=1.2×10-36). In Stage 2, the 23 independent SNPs were examined in stroke cases/non-cases using MORGAM and WTCCC2 collections. SNP rs505922 was nominally associated with ischaemic stroke, odds ratio = 0.94 (95% confidence intervals, 0.88-0.99), p=0.023. Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta=0.066 (0.02) p = 0.001, a finding specific to large vessel and cardioembolic stroke (p = 0.001 and p = <0.001 respectively) but not seen with small vessel stroke (p=0.811).
Interpretation
ABO gene variants are associated with large vessel and cardioembolic stroke but not small vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
doi:10.1002/ana.23838
PMCID: PMC3582024  PMID: 23381943
GWAS; thrombosis; stroke; coagulation factor; stroke subtype
11.  Ischaemic stroke in young adults: predictors of outcome and recurrence 
Background: There is limited information about predictors of outcome and recurrence of ischaemic stroke affecting young adults.
Objective: To assess the predictive value of the presenting characteristics for both outcome and recurrence in young stroke victims.
Methods: Clinical and radiological data for 203 patients aged 16 to 45 years were collected prospectively; they comprised 11% of 1809 consecutive patients with ischaemic stroke. The National Institutes of Health stroke scale (NIHSS), the Bamford criteria, and the trial of ORG 10172 in acute stroke treatment (TOAST) classification were used to define stroke severity, subtype, and aetiology. The clinical outcome of 198 patients (98%) was assessed using the modified Rankin scale (mRS) and categorised as favourable (score 0–1) or unfavourable (score 2–6).
Results: Stroke was caused by atherosclerotic large artery disease in 4%, cardioembolism in 24%, small vessel disease in 9%, another determined aetiology in 30%, and undetermined aetiology in 33%. Clinical outcome at three months was favourable in 68%, unfavourable in 29%, and lethal in 3%. Thirteen non-fatal stroke, two fatal strokes, and six transient ischaemic attacks (TIA) occurred during a mean (SD) follow up of 26 (17) months. High NIHSS score, total anterior circulation stroke, and diabetes mellitus were independent predictors of unfavourable outcome or death (p<0.0001, p = 0.011, and p = 0.023). History of TIA predicted stroke recurrence (p = 0.02).
Conclusions: Severe neurological deficits at presentation, total anterior circulation stroke, and diabetes mellitus predict unfavourable outcome. Previous TIA are associated with increased risk of recurrence.
doi:10.1136/jnnp.2004.040543
PMCID: PMC1739502  PMID: 15654030
12.  Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk 
PLoS Genetics  2010;6(12):e1001233.
Human genome-wide association studies have linked single nucleotide polymorphisms (SNPs) on chromosome 9p21.3 near the INK4/ARF (CDKN2a/b) locus with susceptibility to atherosclerotic vascular disease (ASVD). Although this locus encodes three well-characterized tumor suppressors, p16INK4a, p15INK4b, and ARF, the SNPs most strongly associated with ASVD are ∼120 kb from the nearest coding gene within a long non-coding RNA (ncRNA) known as ANRIL (CDKN2BAS). While individuals homozygous for the atherosclerotic risk allele show decreased expression of ANRIL and the coding INK4/ARF transcripts, the mechanism by which such distant genetic variants influence INK4/ARF expression is unknown. Here, using rapid amplification of cDNA ends (RACE) and analysis of next-generation RNA sequencing datasets, we determined the structure and abundance of multiple ANRIL species. Each of these species was present at very low copy numbers in primary and cultured cells; however, only the expression of ANRIL isoforms containing exons proximal to the INK4/ARF locus correlated with the ASVD risk alleles. Surprisingly, RACE also identified transcripts containing non-colinear ANRIL exonic sequences, whose expression also correlated with genotype and INK4/ARF expression. These non-polyadenylated RNAs resisted RNAse R digestion and could be PCR amplified using outward-facing primers, suggesting they represent circular RNA structures that could arise from by-products of mRNA splicing. Next-generation DNA sequencing and splice prediction algorithms identified polymorphisms within the ASVD risk interval that may regulate ANRIL splicing and circular ANRIL (cANRIL) production. These results identify novel circular RNA products emanating from the ANRIL locus and suggest causal variants at 9p21.3 regulate INK4/ARF expression and ASVD risk by modulating ANRIL expression and/or structure.
Author Summary
Unbiased studies of the human genome have identified strong genetic determinants of atherosclerotic vascular disease (ASVD) on chromosome 9p21.3. This region of the genome does not encode genes previously linked to ASVD, but does contain the INK4/ARF tumor suppressor locus. Products of the INK4/ARF locus regulate cell division, a process thought to be important in ASVD pathology. We and others have suggested that genetic variants in 9p21.3 influence INK4/ARF gene expression; however, the mechanisms by which these distant polymorphisms (>100,000 bp away) influence transcription of the locus is unknown. The ASVD–associated genetic variants lie within the predicted structure of a non-coding RNA (ncRNA) called ANRIL. Based upon recent work suggesting that other ncRNAs can repress nearby coding genes, we considered the possibility that ANRIL structure may regulate INK4/ARF gene expression. Coupling molecular analysis with state-of-the-art sequencing technologies in a wide variety of cell types from normal human donors and cancer cells, we found that ANRIL encodes a heterogeneous species of rare RNA transcripts. Moreover, we identified novel, circular ANRIL isoforms (cANRIL) whose expression correlated with INK4/ARF transcription and ASVD risk. These studies suggest a new model wherein ANRIL structure influences INK4/ARF expression and susceptibility to atherosclerosis.
doi:10.1371/journal.pgen.1001233
PMCID: PMC2996334  PMID: 21151960
13.  Relation Between Left Atrial Enlargement and Stroke Subtypes in Acute Ischemic Stroke Patients 
Objective
Increased atrial size is frequently seen in ischemic stroke patients in clinical practice. There is controversy about whether left atrial enlargement (LAE) should be regarded as a risk factor for cerebral infarction. We investigated the association between indexed left atrial volume (LAVI) and conventional stroke risk factors as well as stroke subtypes in acute ischemic stroke patients.
Methods
One hundred eighty two acute cerebral infarction patients were included in this study. Brain magnetic resonance imaging and transthoracic echocardiography were done for all patients within 30 days of diagnosis of acute cerebral infarction. Echocardiographic LAE was identified when LAVI was more than 27 mL/m2. Stroke subtypes were classified by the Trial of Org 10171 in acute stroke treatment classification.
Results
There were significant differences between subjects with normal and increased LAVI in prevalence of stroke risk factors including atrial fibrillation (p = 0.001), hypertension (p = 0.000), valvular heart disease (p = 0.011) and previous stroke (p = 0.031). An increased LAVI was associated with cardioembolic subtype with an adjusted odds ratio was 6.749 (p = 0.002) compared with small vessel disease.
Conclusion
Increased LAVI was more prevalent in those who had cardiovascular risk factors, such as atrial fibrillation, hypertension, valvular heart disease and history of previous stroke. LAE influenced most patients in all subtypes of ischemic stroke but was most prevalent in the cardioembolic stroke subtype. Increased LAVI might be a risk factor of cerebral infarction, especially in patients with cardioembolic stroke subtype.
doi:10.7461/jcen.2013.15.3.131
PMCID: PMC3804648  PMID: 24167790
Left atrial enlargement; Ischemic stroke; Stroke subtype; Echocardiography
14.  The PlA1/A2 Polymorphism of Glycoprotein IIIa as a Risk Factor for Stroke: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(7):e100239.
Background
The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been reported to be associated with risk of stroke in some studies, although other studies suggest no such association. This meta-analysis and systematic review was conducted to investigate the hypothesis that carriage of the PlA2 allele is a risk factor for stroke.
Methods
Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating carriage of the PlA2 allele and the incidence of stroke. Pooled odds ratios (ORs) were calculated using fixed-effect and random-effect models.
Findings
A total of 35 articles were eligible for inclusion, of which 25 studies were suitable for statistical analysis. For carriage of the PlA2 allele, OR 1.12 (n = 11,873; 95% CI = 1.03–1.22; p = 0.011) was observed for the incidence of stroke in adults, with subgroup analyses identifying the association driven by stroke of an ischaemic (n = 10,494; OR = 1.15, 95% CI = 1.05–1.27; p = 0.003) but not haemorrhagic aetiology (n = 2,470; OR = 0.90, 95% CI = 0.71–1.14; p = 0.398). This association with ischaemic stroke was strongest in individuals homozygous for the PlA2 allele compared to those homozygous for wild-type PlA1 (n = 5,906; OR = 1.74, 95% CI = 1.34–2.26; p<0.001). Subgroup analysis of ischaemic stroke subtypes revealed an increased association with stroke of cardioembolic (n = 1,271; OR 1.56, 95% CI 1.14–2.12; p = 0.005) and large vessel (n = 1,394; OR = 1.76, 95% CI 1.34–2.31; p<0.001) aetiology, but not those of small vessel origin (n = 1,356; OR = 0.99, 95% CI 0.74–1.33; p = 0.950). Egger's regression test suggested a low probability of publication bias for all analyses (p>0.05).
Conclusions
The totality of published data supports the hypothesis that carriage of the PlA2 polymorphism of GPIIIa is a risk factor for ischaemic strokes, and specifically those of cardioembolic and large vessel origin.
doi:10.1371/journal.pone.0100239
PMCID: PMC4079245  PMID: 24988537
15.  Ischemic Stroke Is Associated with the ABO Locus: The EuroCLOT Study 
Annals of Neurology  2013;73(1):16-31.
Objective
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Methods
Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).
Results
Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10–8) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10–186), rs10665 with FVII (p = 2.4 × 10–47), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10–57) and factor VIII (p = 1.2 × 10–36). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88–0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).
Interpretation
ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Ann Neurol 2013
doi:10.1002/ana.23838
PMCID: PMC3582024  PMID: 23381943
16.  Epidemiology of stroke in Northern Italy: the Cerebrovascular Aosta Registry, 2004–2008 
Neurological Sciences  2012;34(7):1071-1081.
Our aim was to prospectively ascertain the incidence of first-ever stroke and ischaemic stroke subtypes, mortality, functional outcome and recurrence in Northern Italy. We identified all possible cases of stroke (1st January 2004 and 31st December 2008). Multiple overlapping sources were used. Standard definitions for incident cases, pathological types and infarction subtypes were used. Patient characteristics were identified and analysed, case-fatality was ascertained from administrative databases, and outcome was assessed in all surviving patients by modified Rankin Scale. We identified 1,326 incident strokes. The pathological diagnosis was confirmed in 94 % of cases. The incidence of first-ever stroke was 80.2 per 100,000 (95 % CI 73–87) when adjusted to world population. The incidence of embolic stroke was significantly greater in women than in men (p < 0.001) whereas the incidence of atherothrombotic stroke was significantly greater in men than in women (p < 0.001). The case-fatality of incident strokes was 9.5 % at 7 day, 16.1 % at 28 day, and 29.9 % at 1 year. Case-fatality of ischaemic stroke was lower than that of other pathological types (p < 0.0001). Hypertension was the most important risk factor, and atrial fibrillation was the most common in embolic stroke. Increasing age, female gender and embolic stroke subtypes were associated with an adverse outcome. Data on stroke incidence and case-fatality were similar to those of other high-income countries. However, differences were found in the distribution of risk factors and prognosis across the stroke types and ischaemic stroke subtypes. Gender differences in long-term functional outcomes were significant.
doi:10.1007/s10072-012-1185-8
PMCID: PMC3719005  PMID: 23007380
First-ever stroke; Ischaemic stroke subtypes; Population-based study; Case-fatality; Long-term functional outcomes
17.  Comorbidity associated with atrial fibrillation: a general practice-based study. 
BACKGROND: Atrial fibrillation is an important risk factor for ischaemic stroke. Anticoagulation treatment with warfarin can substantially reduce the risk of stroke in people with atrial fibrillation but concerns about their side-effects have limited their use in clinical practice. However there has been little population-based research on the comorbidity associated with atrial fibrillation and on the prevalence of potential contraindications to anticoagulantion treatment among these patients. AIM: To determine the prevalence of known risk factors for ischaemic stroke and possible contraindications to anticoagulant treatment among patients with atrial fibrillation. METHOD: One-year prospective cohort study in 60 general practices in England and Wales with a total population of 502,493 people. Age and sex specific prevalence rates and relative risks of risk factors for ischaemic stroke and possible contraindications to antithrombotic treatment were calculated. RESULTS: The number of patients who had a diagnosis of atrial fibrillation during the year was 1,414 (0.3%) patients. The prevalence of other nsk factors for ischaemic stroke in patients with atrial fibrillation increased with age in men, from 48% (relative risk [RR] = 3.78, 95% confidence interval [95% CI] = 3.23-4.41) at 45 to 64 years to 64% (RR = 2.21, 95% CI = 2.00-2.44) at 75years and over A similar increase of 50% (RR = 4.36, 95% CI = 3.54-5.38) to 60% (RR = 2.07, 95% CI = 1.91-2.23) was seen in women. The percentage of men with atrial fibrillation with at least one contraindication to antithrombotic treatment was 5% at 45 to 64 years and 14% at 75 years and over. Among women with atrial fibrillation, 7% had a contraindication at 45 to 64 years and 16% at 75 years and over. The all-ages relative risk of a contraindication was 1.17 (95% CI = 0.92-1.48) in men and 1.53 (95% CI = 1.28-1.83) in women. Forty per cent (575) of patients with atrial fibrillation had at least one risk factor for ischaemic stroke and no contraindications to antithrombotic treatment. CONCLUSION: Atrial fibrillation is associated with a substantial increase in the prevalence of risk factors for ischaemic stroke. By contrast, potential contraindications for antithrombotic treatment are more evenly distributed among patients with and without atrial fibrillation. Around 40% of patients with atrial fibrillation in primary care are at high risk of stroke and have no contraindicationsfor antithrombotic treatment.
PMCID: PMC1314144  PMID: 11761201
18.  Genome wide analysis of blood pressure variability and ischemic stroke 
Background and Purpose
Visit-to-visit variability in BP is associated with ischemic stroke. We sought to determine whether such variability has a genetic aetiology and whether genetic variants associated with BP variability are also associated with ischemic stroke.
Methods
A GWAS for loci influencing BP variability was undertaken in 3,802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study where long-term visit-to-visit and within visit BP measures were available. Since BP variability is strongly associated with ischemic stroke, we genotyped the sentinel SNP in an independent ischemic stroke population comprising of 8,624 cases and 12,722 controls and in 3,900 additional (Scandinavian) participants from the ASCOT study in order to replicate our findings.
Results
The ASCOT discovery GWAS identified a cluster of 17 correlated SNPs within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (p=1.4×10−8). Conditional analysis on rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in ischemic stroke patients found no association for overall stroke (OR 1.02; 95% CI 0.97-1.07; p=0.52) or its sub-types: CE (OR 1.07; 95% CI 0.97-1.16; p=0.17), LVD (OR 0.98; 95% 0.89-1.07; p=0.60) and SVD (OR 1.07; 95% CI 0.97-1.17; p=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (p=0.18).
Conclusions
We identified a cluster of SNPs at the NLGN1 locus showing significant association with BP variability. Follow up analyses did not support an association with risk of ischemic stroke and its subtypes.
doi:10.1161/STROKEAHA.113.002186
PMCID: PMC3904673  PMID: 23929743
Blood pressure variability; stroke; GWAS; gene; polymorphism
19.  Signatures of cardioembolic and large vessel ischemic stroke 
Annals of neurology  2010;68(5):681-692.
Objective
The cause of stroke remains unknown or cryptogenic in many patients. We sought to determine whether gene expression signatures in blood can distinguish between cardioembolic and large vessel causes of stroke, and whether these profiles can predict stroke etiology in the cryptogenic group.
Methods
A total of 194 samples from 76 acute ischemic stroke patients were analyzed. RNA was isolated from blood and run on Affymetrix U133 Plus2.0 microarrays. Genes that distinguish large vessel from cardioembolic stroke were determined at 3, 5, and 24 hours following stroke onset. Predictors were evaluated using cross-validation and a separate set of patients with known stroke subtype. The cause of cryptogenic stroke was predicted based on a model developed from strokes of known cause and identified predictors.
Results
A 40 gene profile differentiated cardioembolic stroke from large vessel stroke with >95% sensitivity and specificity. A separate 37 gene profile differentiated cardioembolic stroke due to atrial fibrillation from non-atrial fibrillation causes with >90% sensitivity and specificity. The identified genes elucidate differences in inflammation between stroke subtypes. When applied to patients with cryptogenic stroke, 17% are predicted to be large vessel and 41% to be cardioembolic stroke. Of the cryptogenic strokes predicted to be cardioembolic, 27% were predicted to have atrial fibrillation.
Interpretation
Gene expression signatures distinguish cardioembolic from large vessel causes of ischemic stroke. These gene profiles may add valuable diagnostic information in the management of patients with stroke of unknown etiology though they need to be validated in future independent, large studies.
doi:10.1002/ana.22187
PMCID: PMC2967466  PMID: 21031583
Gene expression; ischemic stroke; biomarker
20.  Genetics of Common Polygenic Ischaemic Stroke: Current Understanding and Future Challenges 
Stroke Research and Treatment  2011;2011:179061.
Stroke is the third commonest cause of death and the major cause of adult neurological disability worldwide. While much is known about conventional risk factors such as hypertension, diabetes and incidence of smoking, these environmental factors only account for a proportion of stroke risk. Up to 50% of stroke risk can be attributed to genetic risk factors, although to date no single risk allele has been convincingly identified as contributing to this risk. Advances in the field of genetics, most notably genome wide association studies (GWAS), have revealed genetic risks in other cardiovascular disease and these techniques are now being applied to ischaemic stroke. This paper covers previous genetic studies in stroke including candidate gene studies, discusses the genome wide association approach, and future techniques such as next generation sequencing and the post-GWAS era. The review also considers the overlap from other cardiovascular diseases and whether findings from these may also be informative in ischaemic stroke.
doi:10.4061/2011/179061
PMCID: PMC3153917  PMID: 21912753
21.  Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12 
Neurology  2014;83(8):678-685.
Objectives:
To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.
Methods:
Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico “look-up” of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.
Results:
In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07–1.13], p = 7.12 × 10−11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90–1.17], p = 0.695).
Conclusion:
Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
doi:10.1212/WNL.0000000000000707
PMCID: PMC4150131  PMID: 25031287
22.  Uncovering Treatment Burden as a Key Concept for Stroke Care: A Systematic Review of Qualitative Research 
PLoS Medicine  2013;10(6):e1001473.
In a systematic review of qualitative research, Katie Gallacher and colleagues examine the evidence related to treatment burden after stroke from the patient perspective.
Please see later in the article for the Editors' Summary
Background
Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.
Methods and Findings
The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.
Conclusions
Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems.
Systematic Review Registration
International Prospective Register of Systematic Reviews CRD42011001123
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people have a stroke. About 5 million of these people die within a few days, and another 5 million are left disabled. Stroke occurs when the blood supply of the brain is suddenly interrupted by a blood vessel in the brain being blocked by a blood clot (ischemic stroke) or bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. In the longer term, post-stroke rehabilitation can help individuals overcome the physical disabilities caused by stroke, and drugs that thin the blood, reduce blood pressure and reduce cholesterol (major risk factors for stroke) alongside behavioral counseling can reduce the risk of a second stroke.
Why Was This Study Done?
Treatment for, and rehabilitation from, stroke is a lengthy process that requires considerable personal investment from the patient. The term “treatment burden” describes the self-care practices that patients with stroke and other chronic diseases must perform to follow the complicated management strategies that have been developed for these conditions. Unfortunately, treatment burden can overwhelm patients. They may be unable to cope with the multiple demands placed on them by health-care providers and systems for their self-care, a situation that leads to poor adherence to therapies and poor outcomes. For example, patients may find it hard to complete all the exercises designed to help them regain full movement of their limbs after a stroke. Treatment burden has been poorly examined in relation to stroke. Here, the researchers identify and describe the treatment burden in stroke by undertaking a systematic review (a study that uses predefined criteria to identify all the literature on a given topic) of qualitative studies on the patient experience of stroke management. Qualitative studies collect non-quantitative data so, for example, a qualitative study on stroke treatment might ask people how the treatment made them feel whereas a quantitative study might compare clinical outcomes between those receiving and not receiving the treatment.
What Did the Researchers Do and Find?
The researchers identified 69 qualitative studies dealing with the experiences of stroke management of adult patients and analyzed the data in these papers using framework synthesis—an approach that divides data into thematic categories. Specifically, the researchers used a coding framework informed by normalization process theory, a sociological theory of the implementation, embedding and integration of tasks and practices; embedding is the process of making tasks and practices a routine part of everyday life and integration refers to sustaining these embedded practices. The researchers identified four main areas of treatment burden for stroke: making sense of stroke management and planning care; interacting with others, including health care professionals, family and other patients with stroke; enacting management strategies (including enduring institutional admissions, managing stroke in the community, reintegrating into society and adjusting to life after stroke); and reflecting on management to make decisions about self-care. Moreover, they identified problems in all these areas, including inadequate provision of information, poor communication with health-care providers, and unsatisfactory inpatient care.
What Do These Findings Mean?
These findings show that stroke management is extremely demanding for patients and is influenced by both the micro and macro organization of health services. At the micro organizational level, fragmented care and poor communication between patients and clinicians and between health-care providers can mean patients are ill equipped to organize their care and develop coping strategies, which makes adherence to management strategies less likely. At the macro organizational level, it can be hard for patients to obtain the practical and financial help they need to manage their stroke in the community. Overall, these findings suggest that care provision for stroke needs to be transformed so that the needs of patients rather than the needs of health-care systems are prioritized. Further work is required, however, to understand how the patient experience of treatment burden is affected by the clinical characteristics of stroke, by disability level, and by other co-existing diseases. By undertaking such work, it should be possible to generate a patient-reported outcome measure of treatment burden that, if used by policy makers and health-care providers, has the potential to improve the quality of stroke care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001473.
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation including personal stories (in English and Spanish); the US National Institutes of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices website also provides information about stroke for patients and their families, including personal stories
MedlinePlus has links to additional resources about stroke (in English and Spanish)
The UK not-for-profit website Healthtalkonline provides personal stories about stroke
Wikipedia provides information on the burden of treatment and on the normalization process theory (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001473
PMCID: PMC3692487  PMID: 23824703
23.  Infarction in the territory of the anterior cerebral artery: clinical study of 51 patients 
BMC Neurology  2009;9:30.
Background
Little is known about clinical features and prognosis of patients with ischaemic stroke caused by infarction in the territory of the anterior cerebral artery (ACA). This single centre, retrospective study was conducted with the following objectives: a) to describe the clinical characteristics and short-term outcome of stroke patients with ACA infarction as compared with that of patients with ischaemic stroke due to middle cerebral artery (MCA) and posterior cerebral artery (PCA) infarctions, and b) to identify predictors of ACA stroke.
Methods
Fifty-one patients with ACA stroke were included in the "Sagrat Cor Hospital of Barcelona Stroke Registry" during a period of 19 years (1986–2004). Data from stroke patients are entered in the stroke registry following a standardized protocol with 161 items regarding demographics, risk factors, clinical features, laboratory and neuroimaging data, complications and outcome. The characteristics of these 51 patients with ACA stroke were compared with those of the 1355 patients with MCA infarctions and 232 patients with PCA infarctions included in the registry.
Results
Infarctions of the ACA accounted for 1.3% of all cases of stroke (n = 3808) and 1.8% of cerebral infarctions (n = 2704). Stroke subtypes included cardioembolic infarction in 45.1% of patients, atherothrombotic infarction in 29.4%, lacunar infarct in 11.8%, infarct of unknown cause in 11.8% and infarction of unusual aetiology in 2%. In-hospital mortality was 7.8% (n = 4). Only 5 (9.8%) patients were symptom-free at hospital discharge. Speech disturbances (odds ratio [OR] = 0.48) and altered consciousness (OR = 0.31) were independent variables of ACA stroke in comparison with MCA infarction, whereas limb weakness (OR = 9.11), cardioembolism as stroke mechanism (OR = 2.49) and sensory deficit (OR = 0.35) were independent variables associated with ACA stroke in comparison with PCA infarction.
Conclusion
Cardioembolism is the main cause of brain infarction in the territory of the ACA. Several clinical features are more frequent in stroke patients with ACA infarction than in patients with ischaemic stroke due to infarction in the MCA and PCA territories.
doi:10.1186/1471-2377-9-30
PMCID: PMC2714497  PMID: 19589132
24.  Acute Cardioembolic Cerebral Infarction: Answers to Clinical Questions* 
Current Cardiology Reviews  2012;8(1):54-67.
Cardioembolic cerebral infarction (CI) is the most severe subtype of ischaemic stroke but some clinical aspects of this condition are still unclear. This article provides the reader with an overview and up-date of relevant aspects related to clinical features, specific cardiac disorders and prognosis of CI. CI accounts for 14−30% of ischemic strokes; patients with CI are prone to early and long-term stroke recurrence, although recurrences may be preventable by appropriate treatment during the acute phase and strict control at follow-up. Certain clinical features are suggestive of CI, including sudden onset to maximal deficit, decreased level of consciousness at onset, Wernicke’s aphasia or global aphasia without hemiparesis, a Valsalva manoeuvre at the time of stroke onset, and co-occurrence of cerebral and systemic emboli. Lacunar clinical presentations, a lacunar infarct and especially multiple lacunar infarcts, make cardioembolic origin unlikely. The most common disorders associated with a high risk of cardioembolism include atrial fibrillation, recent myocardial infarction, mechanical prosthetic valve, dilated myocardiopathy and mitral rheumatic stenosis. Patent foramen ovale and complex atheromatosis of the aortic arch are potentially emerging sources of cardioembolic infarction. Mitral annular calcification can be a marker of complex aortic atheroma in stroke patients of unkown etiology. Transthoracic and transesophageal echocardiogram can disclose structural heart diseases. Paroxysmal atrial dysrhyhtmia can be detected by Holter monitoring. Magnetic resonance imaging, transcranial Doppler, and electrophysiological studies are useful to document the source of cardioembolism. In-hospital mortality in cardioembolic stroke (27.3%, in our series) is the highest as compared with other subtypes of cerebral infarction. Secondary prevention with anticoagulants should be started immediately if possible in patients at high risk for recurrent cardioembolic stroke in which contraindications, such as falls, poor compliance, uncontrolled epilepsy or gastrointestinal bleeding are absent. Dabigatran has been shown to be non-inferior to warfarin in the prevention of stroke or systemic embolism. All significant structural defects, such as atrial septal defects, vegetations on valve or severe aortic disease should be treated. Aspirin is recommended in stroke patients with a patent foramen ovale and indications of closure should be individualized. CI is an important topic in the frontier between cardiology and vascular neurology, occurs frequently in daily practice, has a high impact for patients, and health care systems and merits an update review of current clinical issues, advances and controversies.
doi:10.2174/157340312801215791
PMCID: PMC3394108  PMID: 22845816
Cardioembolic stroke; recurrent embolization; atrial fibrillation; cardiac source of emboli; outcome; oral anticoagulation; heart failure.
25.  Common Mitochondrial Sequence Variants in Ischemic Stroke 
Annals of neurology  2010;69(3):471-480.
Objective
Rare mitochondrial mutations cause neurologic disease including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV).
Methods
In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke.
Results
No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (OR = 1.13, p < 0.0001) with minimal heterogeneity (I2 = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037).
Interpretation
In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease.
doi:10.1002/ana.22108
PMCID: PMC3003764  PMID: 20839239
mitochondria; stroke; genes; GWAS; white matter

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