Genetics of ischemic stroke

Genetic factors are important in the pathogenesis of cerebrovascular diseases. Stroke represents a multifactorial polygenic disorder where the role of environmental factors is quite well defined as opposed to the role of genetic factors which needs to be further elucidated. Several genes affecting hemostasis, renin-angiotensin system, nitric oxide production, homocysteine metabolism and lipid metabolism have been investigated in stroke even if with conflicting results. The genetic approach could permit, in the future, a better characterization of stroke patients and a more effective individual preventive and therapeutic approach.     

In the search for stroke genes: a long and winding road

In spite of a significant improvement in control of numerous predisposing risk factors, stroke remains a major health problem and a common cause of death and disability in our societies. Genetic predisposition to stroke development exists and has been documented in both animal models and in humans. However, a precise definition of genetic factors responsible for common forms of stroke is still lacking, mainly due to its complex nature, the confounding presence of other predisposing risk factors, and the genetic heterogeneity of human populations. In contrast, important breakthroughs have been reached for monogenic forms of stroke, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).An animal model of stroke, the stroke-prone spontaneously hypertensive rat, has provided valuable information on genetic factors involved in stroke predisposition. Among them, the gene-encoding atrial natriuretic peptide has been identified as a stroke gene in both the stroke-prone spontaneously hypertensive rat and, subsequently, in two different human populations. In particular, structural alterations of the gene are consistently present in diseased individuals, suggesting an important role of mutation-dependent mechanisms in stroke predisposition. Finally, the recent use of intermediate disease phenotypes provides a reductionist approach that may contribute to important accumulating information on genes contributing to cerebrovascular accidents.     

Introduction: Stockholm stroke symposium – from genes to acute care

Abstract. Wester P (Umeå University, Sweden). Introduction: Stockholm stroke symposium – from genes to acute care. J Intern Med 2010; 267: 136–138. The acute stroke research field is dynamic and exciting with several clinical breakthroughs, which give reason for optimism. There is gradually a broader understanding of the genetic linkage with different aspects of stroke. As a majority of stroke cases are caused by thrombo‐embolism with blocking of one or more of the cerebral arteries, the obvious acute treatment strategy is to remove the occluded vessel and thereby restore the aerobic metabolism provided that neuroimaging analyses reveal the presence of rescuable ischaemic tissue. On January 28–29, 2009, the Journal of Internal Medicine arranged a 2‐day symposium entitled Stockholm stroke symposium – from genes to acute care. In this issue of JIM, five comprehensive reviews from this symposium are presented. These include the genetic factors in the aetiology and treatment of ischaemic stroke, the interplay between microvessels, neurons and glia (i.e., the microvascular unit) in the setting of acute stroke, a critical review of various neuroimaging techniques to visualize ischaemic tissue that is still viable (the ischaemic penumbra), recanalization strategies by means of intravenous thrombolysis as well as future recanalization techniques by, for example, intra‐arterial or mechanical thrombolysis and sonothrombolysis by a transcranial approach.     

颅内动脉狭窄的遗传学研究进展

随着CT血管成像(CTA)、磁共振血管成像(MRA)、数字减影血管造影技术(DSA)等检查普及,颅内动脉狭窄的检出率提高,从无症状到头昏等轻微症状,再到卒中发作,均可作为颅内动脉狭窄的临床表现。作为一个多病因疾病,其发病机制复杂,且缺血性卒中复发率高,逐渐受到研究者的关注。颅内动脉狭窄的患者存在年龄分布、性别及种族等差异,提示遗传因素在其中有着重要作用。目前关于颅内动脉狭窄遗传因素方面的研究取得一些进展。     

Genes for left ventricular hypertrophy

Left ventricular (LV) hypertrophy is very common, particularly among hypertensives. The presence of LV hypertrophy profoundly affects morbidity and mortality from cardiovascular diseases and stroke, and is now recognized as the most important predictor of chronic heart failure. Hypertension, obesity, and diabetes are important determinants of LV hypertrophy, but they fail to identify many individuals with the condition, suggesting that other factors, likely genetic in origin, play a role. Although much research has been undertaken to understand the causes of hypertrophy and the medical treatments that can lead to its regression, much remains unknown about its genetic basis. LV hypertrophy is considered a complex genetic disease, likely representing an interaction of several genes with the environment. The heritability of LV mass, measured as a quantitative trait, falls between 0.3 and 0.7 in different populations, suggesting it has a familial component. Genes encoding proteins involved in LV structure, as well as genes encoding cell signal transduction, hormones, growth factors, calcium homeostasis, substrate metabolism, and blood pressure are likely candidates for the development of common forms of LV hypertrophy. An overview of the pathophysiology of LV hypertrophy and dysfunction is provided, in addition to evidence of the genetic basis for LV hypertrophy in humans and animal models.     

Inherited risk factors for thrombotic diseases in children: the genome-wide perspective

As a result of technological advances in the field of high-throughput genomics, there has been a remarkable transition in studying the nature of complex genetic disorders. The genetic analysis of prothrombotic risk factors has shifted from candidate gene to genome-wide association studies (GWAS) in adults. GWAS established a framework in which up to 90% of common genetic variation can be analyzed in a single experiment. Given the ubiquity of the GWAS approach in the adult population, it will become essential for clinicians and researchers in the field of pediatrics to interpret results derived from genetic high-throughput studies. Here, we review the current knowledge regarding genetic factors affecting prothrombotic risk in children and adults. Advantages and pitfalls of the GWAS approach are discussed, including the use of intermediate phenotypes, deep resequencing, and the differences between family-based and association studies. Intelligently designed and well-powered studies incorporating stringent phenotype assessment will contribute to decipher the genetic basis of stroke and venous thrombosis in children.     

青年缺血性卒中患者的基因突变

缺血性卒中是一种多基因遗传性疾病 ,并由多种危险因素叠加而致发病 ,其发病率和致残率均较高。遗传因素对于青年人缺血性卒中的影响作用较大。文章对与青年人缺血性卒中有关的血小板相关基因、凝血 /纤溶基因、脂代谢基因、同型半胱氨酸代谢基因等作了综述。     

早发冠心病相关脂质代谢基因变异的研究进展

早发冠心病(pCHD)是冠心病的一种特殊临床类型。最新的研究表明,pCHD具有很强的遗传基础,遗传因素约占pCHD发病的50%～60%,其中以脂质代谢基因最为重要。脂质代谢基因变异可导致脂质合成及代谢障碍,并出现以动脉粥样硬化(As)及pCHD为临床特征的一系列疾病。该文旨在对脂质代谢基因变异与pCHD之间的关系进行综述。     

Etiology and pathophysiology of stroke as a complex trait

Stroke (brain attack) is currently the third leading cause of death in Western societies. Recent advances in molecular genetics have finally demonstrated what has long been suggested by the clinical observation, that is, stroke is not only the complication of major pathologic conditions such as atherosclerosis, hypertension, or cardiac diseases, but rather it represents a complex trait itself. Thus, the pathogenesis of stroke is often the result of the combined effects of genes exerting a direct contributory role and of their interactions with several environmental determinants. A genetic dissection of stroke has been attempted in suitable animal models and in humans. With this approach, the genetic defects underlying monogenic disorders associated with stroke were identified. Moreover, important findings have recently highlighted the contribution of genes encoding cardiovascular hormones, such as the atrial natriuretic peptide, for the pathogenesis of multifactorial, polygenic forms of stroke. A more thorough understanding of the fine mechanisms, dependent from mutations within stroke susceptibility genes and underlying the disease pathogenesis, may help to introduce new specific tools to achieve better prevention and treatment of stroke.     

Dementia and Atrial Fibrillation: Pathophysiological Mechanisms and Therapeutic Implications

Atrial fibrillation increases the risk of stroke by a factor of four- to fivefold, and dementia is a common consequence of stroke. However, atrial fibrillation has been associated with cognitive impairment and dementia, even in patients without prior overt stroke. Nonischemic mechanisms include cerebral hypoperfusion, vascular inflammation, brain atrophy, genetic factors, and shared risk factors such as age or hypertension. Critical appraisal of studies evaluating the association between atrial fibrillation and dementia in stroke-free patients reveals that several suffer from methodological issues, such as not including silent stroke or anticoagulation therapy in multivariate analyses. Some studies show a close relationship between atrial fibrillation and dementia due to silent stroke, in the absence of overt stroke. Evidence is accumulating that anticoagulation may be effective to decrease the risk of dementia in atrial fibrillation patients. Overall, the pathogenesis linking atrial fibrillation to dementia is likely multifactorial. Cerebral infarctions, including silent stroke, play a central role. These findings underscore the importance of stroke prevention measures in atrial fibrillation patients.     

Modulation of host lipid metabolism by hepatitis C virus: role of new therapies

It is well established that hepatitis C virus(HCV) infection and replication relies on host lipid metabolism. HCV proteins interact and associate with lipid droplets to facilitate virion assembly and production. Besides,circulating infective particles are associated with verylow-density lipoprotein. On the other hand,higher serum lipid levels have been associated with sustained viral response to pegylated interferon and ribavirin therapy in chronic HCV infection,suggesting a relevant role in viral clearance for host proteins. Host and viral genetic factors play an essential role in chronic infection. Lipid metabolism is hijacked by viral infection and could determine the success of viral replication. Recently development of direct acting antiviral agents has shown a very high efficacy( 90%) in sustained viral response rates even for cirrhotic patients and most of the viral genotypes. HCV RNA clearance induced by Sofosbuvir has been associated with an increased concentration and size of the low-density lipoprotein particles. In this review,host genetic factors,viral factors and the interaction between them will be depicted to clarify the major issues involved in viral infection and lipid metabolism.     

Pharmacogenetics in cardiovascular antithrombotic therapy

Thrombosis is the most important underlying mechanism of coronary heart disease and embolic stroke. Therefore, antithrombotic therapy is commonly used in cardiovascular diseases. Unfortunately, the benefits are limited, and an important proportion of treated patients will suffer a new thrombotic event. Lack of clinical benefits may be related to heterogeneous response to antithrombotic treatment among individuals (inter-individual heterogeneity). Few factors have been identified to be involved in this inter-individual heterogeneity. Recently, pharmacogenetic has emerged as a new field in medicine that tries to identify gene variants able to explain the heterogeneity in patient's response to a drug. Polymorphisms affecting disposition, metabolism, transporters or targets of the drug could modify the individual response to one therapy, and probably its side effects. The present review article explores the genetic influence on antithrombotic drug efficacy, analysing the modulating role of different polymorphisms on individuals' response to drugs commonly used in current day practice.     

Gene-diet interaction in relation to the prevention of obesity and type 2 diabetes: evidence from the Finnish Diabetes Prevention Study

Both genetic and environmental factors are involved in the pathogenesis of obesity and type 2 diabetes. Most of the genetic studies on common obesity are confined to the links between a given gene polymorphism or gene loci and different phenotypes of obesity or anthropometric measures. Some studies indicate that genetic factors modify the weight reduction response to energy restriction or weight gain in the long-term. Only a few studies have focused on gene-diet interaction in the development of type 2 diabetes. The Finnish Diabetes Prevention Study shows (DPS) that the success of a lifestyle intervention depends also on the polymorphisms of those genes, which are suggested to play a role in energy metabolism, lipid metabolism, insulin resistance or insulin secretion. This review deals with selected genes examined so far in the DPS.     

Hormones and homocysteine

Hyperhomocysteinemia is a well-established risk factor for cardiovascular disease. Various factors, both modifiable and non-modifiable, interact with the homocysteine metabolism and determine the plasma homocysteine concentrations. These include genetic abnormalities, age, sex and various nutritional and hormonal determinants, all of which play a role in atherosclerosis and accelerated peripheral and cardio-vascular disease (CVD). Several hormones modulate homocysteine metabolism and hence may play a role in the pathogenesis of CVD. The mechanisms involved are unclear. The association of hyperhomocysteinemia with diabetes mellitus is complex and may explain some of the risk of CVD in diabetics not explained by traditional risk factors. Much conflicting data exists in the literature on the role of insulin on homocysteine metabolism, although insulin affects the enzymes regulating the homocysteine metabolism. Treatment of hyperhomocysteinemia with vitamins lowers plasma homocysteine concentrations. Little data is available on the effect of this intervention on cardiovascular outcomes. This review briefly outlines the homocysteine metabolism, summarizes its hormonal determinants, and discusses the role of hyperhomocysteinemia in diabetes, hyperlipidemia and other endocrine disorders.     

Homocysteine and risk of stroke.

The balance of evidence from observational studies suggests that elevated levels of homocysteine are associated with increased risk of carotid artery disease and stroke. There is, however, a paucity of prospective studies. There are also concerns regarding confounding caused by factors associated with hyperhomocysteinaemia, including renal impairment, an atherogenic diet and cigarette smoking. Homozygosity for a defective thermolabile variant of methylene-tetrahydrofolate reductase, a common genetic polymorphism which results in hyperhomocysteinaemia, has not been consistently linked with stroke or other vascular diseases. Additional prospective studies are required, with sufficient power to characterise the form of the association between homocysteine concentrations and stroke risk, whether linear or threshold, and to study interactions between homocysteine, other dietary markers and established stroke risk factors such as smoking and hypertension. Ultimately, the case for a causal role for elevated levels of homocysteine in vascular disease, including stroke, will depend on data from randomised controlled trials of homocysteine-lowering interventions. Given the high prevalence of hyperhomocysteinaemia in apparently well-nourished populations and the tendency for homocysteine concentrations to increase with age, modest effects of homocysteine on stroke risk will have profound implications for public health.     

Precision Medicine in Weight Loss and Healthy Living

Obesity affects 600 million people globally and over one third of the American population. Along with associated comorbidities, including cardiovascular disease, stroke, diabetes, and cancer; the direct and indirect costs of managing obesity are 21% of the total medical costs. These factors shed light on why developing effective and pragmatic strategies to reduce body weight in obese individuals is a major public health concern. An estimated 60–70% of obese Americans attempt to lose weight each year, with only a small minority able to achieve and maintain long term weight loss. To address this issue a precision medicine approach for weight loss has been considered, which places an emphasis on sustainability and real-world application to individualized therapy. In this article we review weight loss interventions in the context of precision medicine and discuss the role of genetic and epigenetic factors, pharmacological interventions, lifestyle interventions, and bariatric surgery on weight loss.     

The pathophysiology, prevention, and treatment of stroke in sickle cell disease

PURPOSE OF REVIEW: Stroke is one of the most devastating complications of sickle cell disease, but current research has led to improved understanding of its pathogenesis and to new approaches in the prevention of both primary and secondary stroke. This review focuses on advances reported in the past 2 years. RECENT FINDINGS: New concepts in the pathophysiology of central nervous system events in sickle cell disease have centered around hemolytic anemia and nitric oxide metabolism. Genetic risk factors are now being explored. Major improvement in primary stroke prevention has occurred through transcranial Doppler ultrasonography screening, but utilization of this technique is far from optimal. Hydroxyurea is now being tested as an alternative approach to chronic transfusion for secondary stroke prevention through a multicenter trial. Other studies are addressing the management of silent infarcts and nocturnal hypoxemia. SUMMARY: Increased understanding of the etiology and pathogenesis of stroke in sickle cell disease should eventually lead to improved management of all central nervous system complications. Alternative secondary stroke prevention with hydroxyurea may allow patients to avoid dependence on life-long chronic transfusion. Primary stroke prevention through transcranial Doppler ultrasonography screening may ultimately yield a dramatic reduction in the incidence of stroke in sickle cell disease.     

Osteoporosis and gene polymorphism

Osteoporosis is a multifactorial disease for which genetic and environmental factors are determinants. We have been conducting a candidate-gene approach in which polymorphisms of many bone metabolism related genes have been examined in the association study with bone mineral density and fracture incidence. However, the contribution of each gene is small and the major genetic determinants of BMD have not elucidated. Recently, a genome-wide systematic approach has been conducted to find the responsible genes using a genome-wide list of single nucleotide polymorphisms (SNPs). So far, several genes with higher statistical power have been screened out with this approach. The accumulating information of genome science will help understand the pathogenesis of osteoporosis and find the useful ways for the prevention and the treatment of this disease.     

The potential role of genes in nonalcoholic fatty liver disease

Although most people with obesity and type 2 diabetes will have steatosis, only a minority will ever develop nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Family studies suggest that genetic factors are important in disease progression, although dissecting genetic factors playing a role in NASH and fibrosis from those influencing the development established risk factors is difficult.Several approaches can be used to look for genetic factors playing a role in nonalcoholic fatty liver disease (NAFLD). In the future, genome-wide single nucleotide polymorphism (SNP) scanning of cases and controls may become feasible. To date, however,studies have relied on candidate gene, case control, allele association methodology. Recent, and as yet preliminary, studies have reported associations between steatosis severity, NASH, and fibrosis with genes whose products are involved in lipid metabolism,oxidative stress, and endotoxin-cytokine interactions. If confirmed,these associations will enhance understanding of disease pathogenesis,and accordingly, the ability to design effective therapies.     

Genetic factors in the pathogenesis of gastroesophageal reflux disease

Multiple factors play a role in the pathogenesis of gastroesophageal reflux disease (GERD). Two landmark studies showing higher concordance of disease in monozygotic than dizygotic twin pairs suggested the role of host genetic factors in its pathogenesis. Recent studies have shown that genetic polymorphism in genes influencing host’s inflammatory response, drug metabolism, cell cycle regulation, xenobiotic pathways, DNA repair, mutagenesis, esophageal sensory function and gene silencing are associated with risk of GERD and its sequelae—Barrett’s esophagus and esophageal adenocarcinoma. However, more studies on larger sample size are needed before reaching a definite conclusion on the role of an individual gene.