Genetics of stroke

Stroke is the second most common cause of death and the most common cause of disability in developed countries. Stroke is a multi-factorial disease caused by a combination of environmental and genetic factors. Numerous epidemiologic studies have documented a significant genetic component in the occurrence of strokes. Genes encoding products involved in lipid metabolism, thrombosis, and inflammation are believed to be potential genetic factors for stroke. Although a large group of candidate genes have been studied, most of the epidemiological results are conflicting. Studies of stroke as a monogenic disease have made huge progress, and animal models serve as an indispensable tool to dissect the complex genetics of stroke. In the present review, we provide insight into the role of in vivo stroke models for the study of stroke genetics.     

New strategies for the prevention of stroke

1. Stroke is a major cause of disability and death worldwide. It is preferable to prevent stroke rather than to treat it and, for the prevention of stroke, all risk factors relating to stroke need to be understood. The present paper reviews potential new strategies for the prevention of stroke based on findings of new risk factors, as well as classical risk factors. 2. Recently, new risk factors related to stroke were reported, including dysfunction of the arterial baroreflex, pro‐inflammatory cytokines, vitamins and hormone deficiency. Correspondingly, therapies targeting these risk factors where shown to significantly reduce the incidence and/or severity of stroke. 3. Because the genesis of stroke is multifactorial, the prevention of stroke should not target one risk factor only. Combination therapies with drugs acting on different risk factors may be more effective in the prevention of stroke.     

Gene-gene and gene-environment interplay represent specific susceptibility for different types of ischaemic stroke and leukoaraiosis

Stroke is a very frequent entity. It is the third leading cause of death and the leading cause of adult disability in the developed world. At a population level, the common sporadic form of ischaemic stroke is underpinned by both environmental and genetic risk factors. Typically, in clinical practice, environmental risk factors such as hypertension, diabetes mellitus, smoking, alcohol consumption, and other factors, are usually considered to be more important than genetic factors. However, it is the interplay of both environmental and common genetic factors [such as the Leiden V, methylenetetrahydrofolate reductase C677T, apolipopotein E 4, endothelial nitric oxide synthase G894T, angiotensin-converting enzyme I/D and angiotensin II type 1 receptor A1166C mutations and polymorphisms] that leads to the development of ischaemic stroke. Indeed, a complex network of interactions between genetic factors and clinical risk factors can be supposed. This review evaluates the possible roles of gene-gene and gene-environment interactions concerning the above genetic factors in the evolution of ischaemic stroke and leukoaraiosis. A knowledge of the specific genetic patterns which are associated with a significant risk of ischaemic stroke or leukoaraiosis may also draw attention to a large population at an increased risk of circulatory disorders. This may facilitate the choice of more effective and specific prevention on the basis of the genotype.     

Genetics of ischemic and hemorrhagic stroke in Chinese population

Stroke is a major cause of adult death and disability worldwide. Epidemiological and animal studies have provided strong evidence that the pathogenesis of stroke is multi-factorial and induced by a combination of environmental and genetic risk factors, but the identification of individual causative variants remains little known. Genetic influences are likely to be polygenic with small effect sizes, and stroke itself consists of a number of different subtypes which may each have different genetic profiles. In addition, various ethnic populations may have different stroke risk, such as Asian race. The reasons for high risk of stroke among the Chinese, especially hemorrhagic stroke, remain unknown. Most human studies have taken a candidate gene approach using case-control methodology. To be reliably detected, small relative risks require large sample sizes, probably 1000 patients or more. Genome-wide association (GWA) study is an unbiased and comprehensive approach to identify common risk alleles for complex diseases. Recently, a multistage GWA study has identified three loci on chromosomes 2q, 8q and 9p to be associated with intracranial aneurysm in European and Japanese populations. Another GWA finding is the identification of risk variants for cardioembolic stroke on chromosome 4q25 in European populations. In this review, we mainly focus on the results from case-control association studies on genetic factors that play a role in the risk of ischemic and hemorrhagic stroke in Chinese population. The combined effects of multiple susceptibility genes for stroke risk are also summarized.     

Secondary prevention of ischemic stroke

Stroke strikes often suddenly, causes long-term disability and death, and is a huge economical burden for the society, not to mention the human tragedy for the patient and the family. At least 15% of stroke survivors will have a second stroke during the next five years, quarter of which prove out to be fatal within four weeks. Secondary prevention of ischemic stroke (IS) targets at reducing stroke recurrence by means of 1) detection and modification of risk factors, 2) antithrombotic or anticoagulant treatment, and 3) surgical interventions for selected patient subgroups. In this review we will discuss these issues in detail and also offer our personal suggestions for treatment choices. Detecting and treating the modifiable risk factors is the major challenge of secondary prevention of IS.     

Prevention of ischemic stroke: overview of traditional risk factors

Stroke prevails as a common and devastating disease. Epidemiological studies have advanced our understanding of stroke risk factors and clinical trials have demonstrated effective interventions to decrease stroke risk by modifying risk factors. Stroke risk factors are classified as traditional and novel and may be further divided into modifiable and non-modifiable. In this review we discuss select traditional risk factors for ischemic stroke, interventions for primary and secondary prevention and areas of research progress. Stroke treatment should be comprehensive, involving patient, community and medical personnel education, evaluation of individual risk factors and overall stroke risk assessment. Ongoing research is exploring further interventions in the management of traditional risk factors. Future research will expand our knowledge about the contribution of genetic factors to stroke, their interaction with environmental factors and open exciting avenues for the development of new therapies.     

PDE4D gene in the STRK1 region on 5q12: susceptibility gene for ischemic stroke

Stroke is thought to be a multifactorial disease that is affected by several environmental factors and genetic variants. In 2002, a candidate locus for stroke (STRK1) was identified with a significant logarithm of odds (LOD) score at 5q12 in Caucasians, and in 2003, the PDE4D gene was subsequently identified as a susceptibility gene at this locus. Some investigators have recently examined whether polymorphisms in the PDE4D gene are associated with stroke in population studies. Some of these studies have reported the polymorphisms to be associated with a risk of stroke, while others have reported the exact opposite. These discrepancies have been attributed to racial differences or differences in methodologies and analyses. In 2006, a powerful method for isolating the susceptibility region at 5q12 was reported in a haplotype-based case-control study. In the present paper, we review both current issues and progress in the isolation of susceptibility genes for ischemic stroke, with particular emphasis on the PDE4D gene in the STRK1 region of 5q12.     

不同等级医院缺血性脑卒中患者二级预防用药依从性现状研究

目的：调查不同等级医院缺血性脑卒中（IS）患者二级预防用药依从性的现状及影响因素。方法采用访谈形式,收集我院（三级医院）IS患者出院1.5年来二级预防用药情况;收集同期在北京万寿路社区医院（一级医院）门诊处方的IS患者1.5年来二级预防用药情况。结果154例我院IS患者中,抗血小板聚集、降脂药的依从性分别为72.7%、49.3%,合并高血压、糖尿病患者降压、降糖药依从性分别为77.6%、70.3%;167例社区IS患者中,抗血小板聚集、降脂药的依从性分别为79.0%、29.9%,合并高血压、糖尿病患者降压、降糖药依从性分别为93.2%、96.6%。结论IS患者二级预防中抗血小板、降脂、降压、降糖药物的应用都未达标,其中降脂药依从性依从性最差,社区医院尤为明显。三级医院和社区医院IS患者二级预防用药依从性存在差异,医疗付费方式、医生未予处方分别是三级医院及社区医院影响依从性独立危险因素。     

颅内前后循环缺血性卒中危险因素、 卒中机制和梗死模式的对比分析

目的 探讨颅内前后循环动脉粥样硬化性狭窄致缺血性卒中 （IS） 患者危险因素、 卒中机制和梗死模式的差异。方法 回顾性连续纳入2014年12月—2017年12月于我院神经内科住院的颅内动脉粥样硬化性狭窄（intracranial atherosclerotic stenosis, ICAS） 致IS的患者257例。依据责任血管的位置, 分为前循环组170例和后循环组87例。收集患者的临床资料, 分析比较2组患者危险因素、 卒中机制和梗死模式的特点及差异。结果 （1） 前循环组中男性、 吸烟史比例高于后循环组, 而高血压和糖尿病比例、 糖化血红蛋白 （HbA1c） 水平低于后循环组 （均P＜ 0.05）。二分类Logistic回归分析显示, 高血压、 糖尿病、 高HbA1c水平是颅内后循环动脉粥样硬化性狭窄致IS的独立危险因素。（2） 卒中机制的分布, 前循环组低灌注和混合机制的构成比高于后循环组, 而穿支动脉闭塞低于后循环组（均P＜0.05）。（3） 梗死模式的分布, 前循环组单发皮质-皮质下梗死的构成比高于后循环组, 而单发皮质下梗死的构成比低于后循环组 （均P＜0.05）。结论 颅内前后循环IS存在危险因素、 卒中机制和梗死模式的差异。针对不同部位的血管制定不同的防治策略, 可能有利于减少相关IS的发生。     

A more accurate approach to molecular genetics analysis in vascular disease

Vascular disease (VD) and its complications are the leading cause of morbility and death in modern civilisations. Primary VD is a very complex and multifactorial process which is still not well understood. Recent studies provide clear and convincing evidences that genetic risk factors (gene polymorphisms) contribute significantly to the pathogenesis and expression of VD. Thus, we have to analyse the interaction of multiple polymorphisms in multiple genes coding for several proteins involved in the molecular etiopathogenesis of VD. All these polymorphisms are interacting among them, enhancing or antagonizing their pathogenic effects, and at the same time, their final phenotypic expression is constantly modulated by other non-genetic factors (environmental and behavioural). Thus, gene-environment interaction analysis would be crucial for the correct etiopathogenic evaluation. According to a particular assortment of positive and negative gene variants (alleles) present in their genetic pool some individuals develop VD without manifesting very extreme levels of any of the classical risk factors while other individuals remain free of disease despite exposure to several risk factors. Taking into account that this heterogeneity is due to their different genetic susceptibility it is necessary to make an analyse in deep including all genetic polymorphisms which have been involved in the vascular etiopathogenesis in order to design the most appropriate intervention strategy. Using a more accurate genetic polymorphism analysis it would be possible to predict complications in order to make prevention designing an individualized drug therapy on the basis of a person's genetic makeup. However, an accurate genetic testing is not being used as often as it is expected because there are so many polymorphisms to consider and DNA tests available to analyse them are usually dispersed throughout different laboratories because they are not included in an unified protocol. In this sense, DNA-Chip technology used as susceptibility (predisposition) testing has evolved into a powerful tool providing informative data from multiple loci in complex diseases like VD (where multiple genetic alterations contribute, but each on a small scale). This technology could greatly reduce health care costs by reducing the number of useless diagnostic tests making possible the genetic dissection of complex human diseases. The proposed paper will discuss these topics with special emphasis on how genetic polymorphisms influence in the individual susceptibility to develop vascular disease and its complications as well as the way that may affect individual responses to several drugs used in the VD management.     

缺血性脑卒中患者早期康复疗效的影响因素分析

目的 探讨影响缺血性脑卒中(IS)患者早期康复疗效的相关危险因素.方法 共纳入168例IS患者,常规治疗的同时,均给予早期康复治疗,并对早期康复治疗患者中成功康复与未成功康复患者以单因素分析筛选出有统计学意义的危险因素,再应用多因素非条件Logistic回归分析早期康复疗效的独立危险因素.结果 单因素分析显示:年龄(≥60岁)、高血压病史、冠心病病史、糖尿病史、吸烟史、焦虑及抑郁与成功康复呈负相关,生活规律、受教育程度(≥12年)及脑力劳动者与成功康复呈正相关;多因素分析显示:受教育程度(≥12年)(OR=0.12,95％ CI0.03～0.75)、脑力劳动者(OR=0.45,95％ CI 0.37～0.47)是成功康复的保护因素(P＜0.05);而年龄(≥60岁)(OR=2.12,95％ CI 1.21～3.21)、焦虑(OR=2.64,95％ CI 1.82～6.11)及抑郁(OR=1.45,95％ CI 1.13～1.96)是成功康复的独立危险因素(P＜0.05).结论 年龄(≥60岁)、焦虑及抑郁是成功康复的独立危险因素,对早期康复治疗IS患者的危险因素应进行必要的干预.     

Therapeutic options for Parkinson's disease

Parkinson's disease is a multifactorial disease. In early-onset cases, genetic predisposition may play a role, but typical Parkinson's disease is most likely determined by genetic and environmental factors. Since age is a consistent risk factor, an age-dependent cumulative insult mechanism may be responsible for the selective degeneration of nigrostriatal neurons. Although there is no cure, several types of treatments are currently available to substantially reduce the clinical symptoms of Parkinson's disease. An understanding of the age-dependent complex pattern of genetic variation (SNP genotyping) together with the genetic expression profile (using chip technology) of the degenerating neurons and the effect of environmental factors is a prerequisite to deciphering the mechanism of pathogenesis. This understanding may lead to predicting drug response and ultimately to developing preventive medicine at the individual level in the future.     

Stroke pharmacogenomics

Circulatory disease accounts for fifteen million deaths each year, of which stroke accounts for four and a half million- with an estimated nine million stroke survivors annually. The overall incidence rate of stroke is 2 to 2.5 per thousand adults with an approximate prevalence of 5 per thousand and an estimated 5-year risk of stroke recurrence of 15 to 40 percent. Conventional risk factors for stroke include: increasing age, hypertension, diabetes mellitus, smoking, increased body mass index, ischemic heart disease, heart failure, atrial fibrillation and lack of physical activity. Age is the strongest risk factor for both ischemic and haemorrhagic stroke with its incidence doubling for each successive decade after the age of fifty-five years. However, there is a substantial portion of patients with significant cerebrovascular disease who do not have any of these stroke risk-factors, leading to the speculation that there are other factors that have not been identified yet So as to improve diagnosis and treatment strategies, as well as to reduce the related public health burden, it could be helpful to successfully identify its extremely complex genetic determinants (polygenic, multiple genes play a role).

Pharmacogenetics is the field of pharmacology that deals with the influence of genetic variation on drug response by correlating gene expression and gene variants with the efficacy or toxicity of drugs. The principle drugs in stroke medicine are antithrombotics. The aim of this paper was to review the most commonly used drugs for stroke such as rtPA in the acute phase as well as antiplatelets and wafarin for secondary prophylaxis.     

Secondary prevention of stroke: a practical guide to drug treatment

Stroke is a disease of the elderly and, as a result of the expected demographic changes in many industrialised countries, its incidence is likely to increase in the future. A first-ever stroke significantly increases the likelihood of further events; thus, secondary prevention is of major importance. Only a minority of recurrent strokes can be prevented by surgical or other invasive methods, meaning that most secondary preventive measures involve drug treatment, which has become increasingly sophisticated in recent years. Ischaemic stroke constitutes the vast majority of all strokes; effective secondary prevention depends on a variety of factors, of which the correct classification in terms of subtypes and aetiological mechanisms is a pivotal prerequisite, as is the assessment of the patient's cardiovascular risk profile. In addition to the evaluation of pathomechanisms, stratification of subtypes of brain infarction is mainly based on morphology seen with brain imaging techniques, which provides additional evidence for the presumed cause of the stroke. Inhibitors of platelet function and anticoagulants are the two major groups of antithrombotic drugs used for the secondary prevention of stroke. Antiplatelet agents are still indicated in the majority of patients after ischaemic stroke, especially if an arterial origin is presumed. In addition to aspirin (acetylsalicylic acid), the position of which as the first-line antiplatelet drug is increasingly being questioned, other compounds with antiplatelet activity have been developed and have proven effective in secondary stroke prevention, including ticlopidine, clopidogrel and dipyridamole. Anticoagulants are principally indicated after cardioembolic ischaemic stroke; however, their inherent bleeding risks render their use in many cases rather difficult, in particular for elderly patients. Patient compliance with the recommended treatment is of major importance, given the somewhat limited efficacy of antithrombotic agents in stroke prevention. Since 'real world' experience does not match the circumstances under which clinical trials are conducted, this article will also deal with problems not covered by specific studies, such as risk stratification for anticoagulant treatment and how to proceed in cases of unknown stroke aetiology. The management of major cardiovascular risk factors is the other mainstay of secondary stroke prevention. Recent evidence indicates that antihypertensive treatment may be as effective as antithrombotic drugs for secondary prevention of stroke. This still needs to be proven for the treatment of other cardiovascular risk factors, such as diabetes mellitus and hypercholesterolemia. Nevertheless, the results of recent studies investigating the effect of HMG-CoA reductase inhibitors ('statins') on cardiovascular events strongly suggest a stroke-preventive effect.     

Arterial stiffness and stroke in hypertension: therapeutic implications for stroke prevention

Stroke is the second leading cause of mortality worldwide, and the leading cause of death in China and Japan. Its prevention represents a major goal. Identification of primary stroke risk, particularly through newly individualised risk factors including biomarkers of large artery damage such as arterial stiffening, is necessary for determining the appropriate level of intervention. The purpose of this review is to focus on the pathophysiology of arterial stiffness, its predictive value for stroke and the therapeutic implications of this risk factor for stroke prevention. The predictive value of arterial stiffness for stroke was demonstrated in a longitudinal study that included 1715 patients with essential hypertension and measurements of carotid-femoral pulse wave velocity (PWV) [an indicator of arterial stiffness] at entry. Over a mean follow-up period of 7.9 years, during which 25 fatal strokes occurred, PWV significantly predicted stroke (relative risk = 1.39 [(95% CI 1.08, 1.72]; p = 0.02 for each 4 m/sec increase) independently of classical cardiovascular risk factors, including age, cholesterol level, diabetes mellitus, smoking and mean blood pressure. Additional longitudinal studies are needed to confirm the predictive value of aortic stiffness on primary and secondary events, in low- and high-risk populations, in various countries, and using different methodologies of arterial stiffness measurement. Drug treatment could prevent stroke through a reduction in arterial stiffness in parallel with correction of cardiovascular risk factors such as hypertension, dyslipidaemia, diabetes mellitus and smoking, all of which are associated with arterial stiffening. In view of the important local actions of angiotensin II on arterial stiffening, drugs interfering with the renin-angiotensin-aldosterone system should be particularly effective. Promising therapeutic strategies to reduce arterial stiffness include taking advantage of the non-lipid-lowering effects of statins and directly targeting the molecular events leading to arterial stiffening, such as formation of advanced glycation end products.     

Clopidogrel in secondary ischemic stroke prevention

The results obtained in the CAPRIE study in 1996 led to the introduction of the clopidogrel as a new antiplatelet drug in the secondary prevention of acute myocardial infarct (AMI), ischemic stroke (IS) and symptomatic peripheral artery disease (PAD). Clopidogrel showed a similar efficacy and safety than acetylsalicylic acid (ASA). More recently, the combined use of clopidogrel with ASA has evidenced a better protection than ASA alone in some patients: patients with past history of AMI, angina pectoris, intermittent claudication or PAD, IS or TIA, coronary bypass, and diabetes mellitus, patients on treatment with statins, and patients with symptomatic carotid stenosis >/=50%. We review the reported evidence on the efficacy of clopidogrel in the secondary prevention of ischemic stroke.     

Cost-effective intervention in stroke

A rigorous assessment of current practice in all branches of medicine is necessary to ensure that we are minimising the costs and maximising the effectiveness of management and treatment. This is especially important in cerebrovascular disease which imposes a large burden of death; it is the third commonest cause of death after cancer and heart disease in most developed countries, and the commonest cause of long term disability on society. Stroke consumes up to 5% of healthcare expenditure in developed countries, and costs can be expected to remain static or increase with an increase in the proportion of elderly (who are at high risk of stroke) in the community over coming decades. This article reviews the epidemiology of stroke (risk factors, incidence, prevalence and the burden of disability and handicap), the various studies dealing with the community and individual costs of stroke, and the cost-effectiveness of interventions to prevent stroke such as control of hypertension, reduction in cigarette intake, encouragement of a healthy lifestyle, antiplatelet or anticoagulant therapy, and carotid endarterectomy. Acute treatment of stroke remains an area of major potential therapeutic benefit, but no widely applicable therapy currently exists, although many treatments are being investigated. Rehabilitation after stroke is costly, but may result in significant reduction in disability and handicap with reduced need for long term institutional care. The clinical implications of these studies and the potential for future research are also discussed.     

The genetics of small-vessel disease

Cerebral small-vessel disease (SVD) is a well-known cause of stroke, dementia and death, but its pathogenesis is not yet completely understood. The spectrum of neuroradiological manifestations associated with SVD is wide and may result from chronic and diffuse or acute and focal ischemia (leukoaraiosis and lacunar infarction) as well as from small-vessel rupture (cerebral microbleeds and intracerebral hemorrhage). Several lines of evidence from family and twin studies support the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge of SVD pathogenesis and help to identify new therapeutic targets to reduce the burden of SVD-related cognitive decline and stroke disability. A number of monogenic conditions presenting with clinical features of SVD have been described. Although monogenic disorders account for only a small proportion of SVD, study of these diseases may provide further insight into the pathogenesis of SVD. In most cases, however, SVD is thought to be a multifactorial disorder. Several genetic association studies, conducted using the candidate gene and, more recently, the genome-wide approach, have so far failed to demonstrate a convincing association between SVD and genetic variants. Methodological issues, particularly related to inaccurate or heterogeneous phenotyping and insufficient sample sizes, have been invoked as possible reasons for this. Large collaborative efforts and robust replication, as well as implementation of new genetic approaches, are necessary to identify genetic susceptibility factors for complex SVD.     

Advancing stroke therapeutics through genetic understanding

Stroke is a complex neurological disorder that most likely results from an intricate interplay between lifestyle, environment and genetics. Genes can influence susceptibility to stroke, alter responses to pharmacotherapy, and affect disease outcome. Recently, common variations within the PDE4D and ALOX5AP genes have been identified that increase population-attributable risk of stroke in Iceland. These genes are yet to be unequivocally confirmed and the functional variants identified. Characterizing the genetic profile of individuals at highest risk of stroke will permit more targeted pharmacological approaches to early primary and secondary stroke prevention. Pharmacogenomics is likely to be particularly important for stroke prevention because of the narrow therapeutic index for treatments like warfarin that prevents thrombosis but also promotes hemorrhage. Identifying possible genetic determinants of outcome will also open new avenues of research into stroke therapeutics beyond thrombolysis.     

Pharmacogenomics of neurodegenerative diseases

Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease.