Stroke Genetics Research Articles

Next Generation Sequencing for Systematic Assessment of Genetics of Small-Vessel Disease and Lacunar Stroke

The pathogenesis of cerebral small-vessel disease (SVD) is still incompletely understood, although evidence from family and twin studies supports the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge on SVD pathogenesis. SVE-LA (Small Vessel and Lacunar) project is a multicenter prospective Lombardia region study aimed at applying innovative genetic technologies and accurate patient phenotyping to discover the genetic basis of SVD. A continuous series of subjects (aged 15-80years) with a clinically and radiologically defined lacunar stroke referring to the participating Lombardia region stroke centers and an adequate number of age- and sex-matched controls are being included into the study. For each patient, clinical, demographic, instrumental, and familial data are collected applying standardized forms. After informed consent, a DNA sample for genetic analysis from patients and controls has been collected. The next generation sequencing (NGS) technology was applied to systematically screen patients for the most important genetic factors both monogenic and polygenic associated with SVD. The study includes also a centralized quantitative and qualitative analysis of neuroimaging studies. Between March 2011 and October 2013, 212 lacunar stroke patients and 78 controls have been collected. Mean age of cases was 65.8±11.1 years and 67% were men. This is the first study applying systematically NGS technology on a wide series of lacunar stroke patients. A translational approach combining a systematic genetic screening with a detailed phenotyping may facilitate the discovery of genetic basis and improve our knowledge in the pathogenesis of SVD.

Abstract T P191: Using Clinical Trial Data to Generate Causative Classification System (CCS) Ischemic Stroke Phenotypes for the NINDS Stroke Genetics Network (SiGN)

Background: Recruitment and phenotyping constitute major costs in stroke genetics research. Clinical trial datasets that include biological samples provide an opportunity to leverage richly phenotyped cases for genomic research. However, the heterogeneity of stroke and methodological differences across studies present challenges. We developed and validated a systematic method of mapping data abstracted from a multicenter randomized clinical trial to the inputs of the CCS stroke subtyping system for the SiGN study. Methods: The SiGN Phenotype Committee and the Secondary Prevention of Small Subcortical Strokes (SPS3) research team systematically reviewed SPS3 case report forms (CRF) to identify key elements required to generate CCS subtyping, and drafted and refined mapping rules using a derivation set of 30 charts. The resultant algorithm was compared to manual entry of clinical information into the CCS in a test set of 30 randomly selected charts. This identified problems due to multiple versions of CRFs (up to 7 versions) and prompted revision of the mapping rules. We assessed the revised algorithm in an independent test set. Results: None of the subtype classifications agreed in the initial testing prompting revision to allow capture information from different versions of the CRFs. The revised mapping algorithm applied to the same test set performed well; 29/30 agreed - 20 small artery occlusion (SAO) evident, 4 SAO possible, 2 SAO probable and 3 supra-aortic large artery atherosclerosis evident). The one chart that disagreed was classified as SAO evident by manual entry but as undetermined by the data mapping rules. In the 2nd independent test set, 30/30 agreed: 22 SAO evident, 4 SAO possible, 3 supra-aortic large artery atherosclerosis evident and 1 undetermined unknown - incomplete evaluation. Conclusions: We created mapping rules using CRFs from a clinical trial to allow reliable subtype classification using the CCS. Issues related to multiple iterations of CRFs presented challenges. Highly phenotyped stroke cases from clinical trials represent a cost-effective opportunity for genomic research.

Abstract 205: Etiologic Ischemic Stroke Phenotypes in the NINDS Stroke Genetics Network

Background and Purpose: NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of ischemic stroke subtypes. The goal of this analysis is to characterize the etiopathogenetic basis of ischemic stroke in the consortium. Methods: This analysis included 16,954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries. 52 trained and certified adjudicators used the web-based Causative Classification of Stroke System for etiologic stroke classification through chart reviews to determine both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards the most likely cause in the presence of multiple etiologies) and causative subtypes in each subject. Classification reliability was assessed with blinded re-adjudication of 1509 randomly selected cases. Findings: The figure shows the distribution of etiologic categories. Overall, only 40% to 54% of cases with a given major ischemic stroke etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0·72, 95%CI:0·69-0·75) and phenotypic classifications (kappa 0·73, 95%CI:0·70-0·75). Conclusions: This study provides high quality data on etiologic stroke subtypes and demonstrates that etiologic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes suggests that the presence of an abnormality in a stroke patient does not necessarily mean that it is the cause of stroke.

Positive perspectives from proton therapy.

In this issue of the Biomedical Journal, we take a look at some of the benefits of proton therapy, which is an emerging technique in cancer treatment and highlight an animal study, showing that a common fruit ripening agent is toxic when used in excessive doses. Finally, this issue includes reports that shed light on the genetics of stroke and childhood leukemia.

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

Exploring the genetic basis of stroke. Spanish stroke genetics consortium

This article provides an overview of stroke genetics studies ranging from the candidate gene approach to more recent studies by the genome wide association. It highlights the complexity of stroke owing to its different aetiopathogenic mechanisms, the difficulties in studying its genetic component, and the solutions provided to date. The study emphasises the importance of cooperation between the different centres, whether this takes place occasionally or through the creation of lasting consortiums. This strategy is currently essential to the completion of high-quality scientific studies that allow researchers to gain a better knowledge of the genetic component of stroke as it relates to aetiology, treatment, and prevention.

Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study.

The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.

Genetics of ischemic stroke in young adults.

Ischemic stroke (IS) is a complex genetic disorder caused by a combination of multiple genetic and environmental factors. Despite the enormous burden associated with stroke, we know little about its underlying pathogenesis. Unlike many other common age-related diseases (eg, diabetes mellitus and heart disease), there are no good preclinical biomarkers that can provide a foothold for studying the molecular and physiological processes leading up to a stroke event. Because a genetic predisposition to stroke is widely acknowledged, 1 current strategy to study stroke pathogenesis is to start by identifying genes associated with stroke and then to investigate the function of these genes. Toward this goal, numerous candidate gene and genome-wide association studies (GWAS) of stroke have been performed. A strategy successfully used to identify genetic determinants of other common complex diseases has been to focus on subtypes, such as early-onset disease which may be enriched for high-penetrance variants. Variants that are highly penetrant or highly predictive of diseases may be easier to detect and also produce useful insights about disease pathways, even if the same variants play a lesser role in late-onset disease. The goal of this review is to assess the evidence for a genetic basis to early-onset IS. We mainly focus on early-onset stroke occurring between the ages of 15 and 49 years but specify age ranges considered by other studies as they are discussed. We begin with an epidemiological characterization of early-onset stroke, comparing and contrasting risk factors and the heterogeneity of stroke subtypes between early- and late-onset IS. We then review the evidence for a genetic basis of early-onset stroke, contrasting where possible the magnitude of the genetic contribution in younger versus older IS through familial aggregation studies. Finally, we review current status and prospects for identifying genes contributing to susceptibility to early-onset stroke. Throughout the …

Using previously genotyped controls in genome-wide association studies (GWAS): application to the Stroke Genetics Network (SiGN).

Genome-wide association studies (GWAS) are widely applied to identify susceptibility loci for a variety of diseases using genotyping arrays that interrogate known polymorphisms throughout the genome. A particular strength of GWAS is that it is unbiased with respect to specific genomic elements (e.g., coding or regulatory regions of genes), and it has revealed important associations that would have never been suspected based on prior knowledge or assumptions. To date, the discovered SNPs associated with complex human traits tend to have small effect sizes, requiring very large sample sizes to achieve robust statistical power. To address these issues, a number of efficient strategies have emerged for conducting GWAS, including combining study results across multiple studies using meta-analysis, collecting cases through electronic health records, and using samples collected from other studies as controls that have already been genotyped and made publicly available (e.g., through deposition of de-identified data into dbGaP or EGA). In certain scenarios, it may be attractive to use already genotyped controls and divert resources to standardized collection, phenotyping, and genotyping of cases only. This strategy, however, requires that careful attention be paid to the choice of “public controls” and to the comparability of genetic data between cases and the public controls to ensure that any allele frequency differences observed between groups is attributable to locus-specific effects rather than to a systematic bias due to poor matching (population stratification) or differential genotype calling (batch effects). The goal of this paper is to describe some of the potential pitfalls in using previously genotyped control data. We focus on considerations related to the choice of control groups, the use of different genotyping platforms, and approaches to deal with population stratification when cases and controls are genotyped across different platforms.

Prothrombin G20210A Mutation Is Associated With Young-Onset Stroke

Although the prothrombin G20210A mutation has been implicated as a risk factor for venous thrombosis, its role in arterial ischemic stroke is unclear, particularly among young adults. To address this issue, we examined the association between prothrombin G20210A and ischemic stroke in a white case-control population and additionally performed a meta-analysis. From the population-based Genetics of Early Onset Stroke (GEOS) study, we identified 397 individuals of European ancestry aged 15 to 49 years with first-ever ischemic stroke and 426 matched controls. Logistic regression was used to calculate odds ratios (ORs) in the entire population and for subgroups stratified by sex, age, oral contraceptive use, migraine, and smoking status. A meta-analysis of 17 case-control studies (n=2305 cases <55 years) was also performed with and without GEOS data. Within GEOS, the association of the prothrombin G20210A mutation with ischemic stroke did not achieve statistical significance (OR=2.5; 95% confidence interval [CI]=0.9-6.5; P=0.07). However, among adults aged 15 to 42 years (younger than median age), cases were significantly more likely than controls to have the mutation (OR=5.9; 95% CI=1.2-28.1; P=0.03), whereas adults aged 42 to 49 years were not (OR=1.4; 95% CI=0.4-5.1; P=0.94). In our meta-analysis, the mutation was associated with significantly increased stroke risk in adults ≤55 years (OR=1.4; 95% CI=1.1-1.9; P=0.02), with significance increasing with addition of the GEOS results (OR=1.5; 95% CI=1.1-2.0; P=0.005). The prothrombin G20210A mutation is associated with ischemic stroke in young adults and may have an even stronger association among those with earlier onset strokes. Our finding of a stronger association in the younger young adult population requires replication.

In This Issue

HomeCirculation ResearchVol. 114, No. 4In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published14 Feb 2014https://doi.org/10.1161/RES.0000000000000014Circulation Research. 2014;114:587Genetics of Collateral Circulation and Stroke (p 660)Download figureDownload PowerPointSealock et al identify a locus in the mouse genome influencing recovery from ischemic injury.The severity of tissue damage that results from the occlusion of blood vessels is influenced by the number and size of collateral vessels in the tissue. Collateral vessels link arterioles to one another and hence can provide alternative routes for blood flow should one arteriole become blocked. Recently, a genetic locus that controls collateral size and abundance was discovered within a 27 megabase region on chromosome 7 in the mouse. Through genetic mapping techniques, Sealock and colleagues have now narrowed this region from 27 to 0.7 megabases containing just 28 protein-coding genes. Although the specific gene regulating collateral growth has not been identified, the team showed that a version of the locus associated with increased number and size of collaterals also confers improved recovery from ischemic injury in models of stroke and peripheral artery disease. Importantly, the chromosome 7 locus is partially syntenic with a region of chromosome 16 in man. If this chromosome 16 region also has effects on collaterals, and the gene responsible can be identified, it may provide useful information for assessing a person’s risk for ischemia and their ability to recover from it.CRP is not Proinflammatory in Healthy Subjects (p 672)Download figureDownload PowerPointLane et al find that C reactive protein is not proinflammatory.Levels of C reactive protein (CRP) in the blood have long been associated with cardiovascular disease risk. And many of the known factors that cause atherosclerosis also cause levels of CRP to rise. These findings have led to speculation that CRP itself might play a causative role in atherosclerosis. Indeed, studies examining the effect of CRP on human cells in culture, on animals and even on human volunteers have indicated that CRP has a proinflammatory effect. But, Lane and colleagues say that the CRP used in most earlier studies was, a recombinant protein prepared from bacterial cultures. Thus the proinflammatory effects of recombinant CRP may have been caused by bacterial impurities. To test this idea, the team isolated and purified CRP from human plasma and infused this clinical-grade preparation at varying doses into seven healthy adults. By measuring cytokine levels and counting the numbers of neutrophils and platelets in the volunteers after CRP infusion, it was clear that none of the recipients showed any evidence of inflammation. The authors conclude that CRP itself is not proinflammatory and therefore is unlikely to be a useful target for anti-atherosclerosis treatments.Interferon and Pulmonary Arterial Hypertension (p 677)Download figureDownload PowerPointInterferon prompts the development of pulmonary arterial hypertension in mice, report George et al.Pulmonary arterial hypertension (PAH), characterized by increased resistance in the lungs’ vasculature, causes strain to the right side of the heart. Left untreated the condition can ultimately lead to heart failure and death. PAH has been linked to HIV, systemic sclerosis and other conditions in which blood levels of the cytokine interferon are elevated. Furthermore, PAH is also associated with therapeutic use of interferon. Despite the accumulating circumstantial evidence, however, no causative role for interferon in PAH has been established. George and colleagues have now found more evidence of a link between interferon and PAH, showing that systemic sclerosis patients with PAH have higher levels of interferon in the blood and increased expression of an interferon receptor in the lungs of PAH patients when compared with patients without PAH. More importantly, they have also found evidence that interferon signaling is involved in the pathology of PAH. Their experiments showed that mice that lacked an interferon receptor were protected against experimentally induced PAH. These findings provide an explanation for why PAH can develop in patients receiving interferon therapy, and suggest that the interferon pathway may be a useful target for the development of new PAH treatments. Previous Back to top Next FiguresReferencesRelatedDetails February 14, 2014Vol 114, Issue 4 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000014 Originally publishedFebruary 14, 2014 PDF download Advertisement

Abstract 26: Agreement Between TOAST and CCS Classification in SiGN

Background: The heterogeneity of ischemic stroke has relevance for determination of risk for recurrence, prediction of outcomes, and identification of genetic risk factors. Among the many systems created for classifying patients into subtypes of stroke, the Trial of Org10172 Acute Stroke Trial (TOAST) and Causative Classification of Stroke (CCS) systems are among the most commonly used. Both systems generate similar subtype diagnoses although the two systems use different criteria for subtype assignment. The purpose of this study was to assess the level of agreement between subtype classification made using these two systems. Methods: Study subjects included 14,106 adult men and women accrued in the NINDS Stroke Genetics Network (SiGN) across 21 centers in the US and Europe classified independently using both with TOAST and CCS. Kappa statistics were calculated for the five major ischemic stroke subtypes common to both systems. Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; kappa = 0.60, 95% confidence interval [CI], 0.59 to 0.61). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large artery atherosclerosis (kappa, 0.71; 95% CI, 0.70 to 0.73) and lowest for small artery occlusion (kappa = 0.56, 95%CI, 0.54 to 0.58). Conclusion: Agreement between TOAST and CCS diagnoses was only moderate. Caution is warranted when comparing or combining results based upon the two systems. Re-phenotyping using one system should be encouraged when possible to ensure valid results. Table: Cross-classification of stroke subtypes by TOAST and CCS

Abstract W MP67: Etiology-Specific Clinical and Imaging Features in Ischemic Stroke

Background: Identification of clinical and imaging characteristics of ischemic stroke that can predict the underlying etiology is critical for accurate stroke subtyping. We sought to investigate the relationship between stroke characteristics and stroke etiology in 7,591 patients in the NINDS Stroke Genetics Network Study. Methods: We determined the probability of having a major etiology in the presence of certain stroke characteristics that were previously linked to specific stroke mechanisms. We excluded patients with multiple competing major etiologies. All patients had brain imaging, intra- and extra-cranial vascular imaging, and complete cardiac assessment. We defined major etiologies according to the Causative Classification of Stroke System Criteria without reference to the stroke characteristics under study. Results: History of 1 ipsilateral ischemic events within the last month, the presence of internal watershed infarcts or multiple, ipsilateral, unilateral, and temporally separate infarcts were associated with large artery atherosclerosis (Table). Multiple acute infarcts in different cerebral circulations were more common in patients with major cardiac source of embolism as well as in those with uncommon/cryptogenic causes. Stereotypic lacunar TIAs within the last week and lacunar syndrome were associated with lacunar infarction Discussion: Clinical and imaging stroke characteristics appear to predict stroke etiologies. This information may find utility in developing algorithms for a guided stroke evaluation as well as help identify the most likely causative etiology in the presence of multiple competing etiologies.

Abstract T P153: Women and Men with Ischemic Stroke in SiGN Have Different Subtype Distributions and Risk Factors

Introduction: The relative distribution of stroke risk factors, as well as ischemic stroke subtypes, in women compared with men is not well described. Hypothesis: We hypothesized that the distribution of ischemic stroke risk factors and subtypes would differ by sex, with a later onset in women and greater proportion of comorbidities. Methods: The NINDS Stroke Genetics Network (SiGN) consortium was established to evaluate genetic risk factors for ischemic stroke. A total of 23 separate studies performed Causative Classification of Stroke (CCS) typing using standardized criteria on ischemic stroke cases and contributed data on risk factors. We compared the distribution of ischemic stroke risk factors and CCS phenotypes between men and women with ischemic stroke. Results: Of the 16,228 ischemic strokes in SiGN, 8005 (49.3%) occurred in women. Median age at stroke was older in female than male stroke cases (73 vs. 66 years) (p=&lt;0.0001). Among stroke cases, women were more likely than men cases to have hypertension or atrial fibrillation and less likely to have diabetes or coronary artery disease, or to smoke (p &lt;0.003 for all). The distribution of stroke subtypes also differed by sex, with women less likely than men to have large artery infarction and small artery occlusion, and more likely to have cardioembolic stroke and undetermined stroke due to incomplete work-up (p values all &lt;0.0001; see Table). Results were similar when the distribution of stroke subtypes was examined for those &lt;70 years and ≥70 years, except for cardioembolic stroke remaining more common only among women ≥70. Conclusions: In this large group of carefully phenotyped ischemic strokes, the distribution of ischemic stroke subtypes and risk factor profiles differ significantly by sex. Evaluation of the causes of these differences may highlight areas for improved prevention and risk reduction in both genders.

Stroke Genetics: A Review and Update

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.

William L. Young, MD

William L. Young, MD

NOTCH3 Variants and Risk of Ischemic Stroke

BackgroundMutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved.MethodsAll 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS).ResultsSequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series.ConclusionCysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.

Stroke Genetics Network (SiGN) study: design and rationale for a genome-wide association study of ischemic stroke subtypes.

Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

Aproximación al conocimiento de las bases genéticas del ictus. Consorcio español de genética del ictus

This article provides an overview of stroke genetics studies ranging from the candidate gene approach to more recent studies by the genome wide association. It highlights the complexity of stroke owing to its different aetiopathogenic mechanisms, the difficulties in studying its genetic component, and the solutions provided to date. The study emphasises the importance of cooperation between the different centres, whether this takes places occasionally or through the creation of lasting consortiums. This strategy is currently essential to the completion of high-quality scientific studies that allow researchers to gain a better knowledge of the genetic component of stroke as it relates to aetiology, treatment, and prevention.

Genetics of Stroke

HomeStrokeVol. 44, No. 6_suppl_1Genetics of Stroke Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBGenetics of StrokeImpact and Limitations of Evolving Technology: Introduction Daniel Woo, MD and James F. Meschia, MD Daniel WooDaniel Woo From the Department of Neurology, University of Cincinnati, Cincinnati, OH (D.W.); and Department of Neurology, Mayo Clinic, Jacksonville, FL(J.F.M.). Search for more papers by this author and James F. MeschiaJames F. Meschia From the Department of Neurology, University of Cincinnati, Cincinnati, OH (D.W.); and Department of Neurology, Mayo Clinic, Jacksonville, FL(J.F.M.). Search for more papers by this author Originally published1 Jun 2013https://doi.org/10.1161/STROKEAHA.112.680041Stroke. 2013;44:S16There have been advances in understanding the molecular underpinnings of risk and response to stroke hailing from genetic research. Traditional linkage studies were limited to identifying genetic mutations, representing small fractions of human disease burden. Yet with large-scale genotyping, RNA expression studies and microRNA analyses, modern genetic research has opened the possibility of understanding the greater complexity of variation.Saugstad writes of the nascent understanding of microRNAs in ischemic brain injury.1 MicroRNAs regulate messenger RNA (mRNA), the template for all proteins. mRNA levels are under complex regulation. One microRNA can target several mRNAs, and 1 mRNA can be the target of several microRNAs. A normal gene that is dysregulated may lead to diseased or increased risk, just as mutation of a gene may. Adding to the complexity of studying this system is that commercial assays vary in their output, suggesting that more work is needed to optimize and standardize the assays. Despite these complexities, studies suggest that ischemia changes the microRNA environment. Unsurprisingly, on the road to cell death, changes occur in microRNA levels. The crucial question is whether microRNA changes perpetuate or accentuate ischemic injury, or whether the changes are merely a consequence of injury without pathological role. The answer to the cause or consequence question will ultimately determine whether this line of inquiry will translate into effective treatments.Sharp and Jickling provide an update on research examining mRNA content produced by genes.2 Otherwise, normal genes that are upregulated or downregulated may affect disease risk or response to injury. Unknown stroke may represent as much as 40% of ischemic stroke subtypes. Yet, by comparing unknown to known stroke subtypes, Sharp et al suggest that the gene expression profiles of unknown stroke most often seem most like that of cardioembolic stroke. Expression profiling might also help differentiate true transient ischemic attack from nonischemic events.Genome-wide association studies have yielded at least 8 loci for intracranial aneurysms. Foroud et al performed whole-exome sequencing in a handful of highly selected multiplex families (50 individuals) with intracranial aneurysms.3 Exome sequencing examines all exons within the human genome and can evaluate not only the risk of a single variation but also the burden of variants within a gene. After filtering, 96 candidate genes were identified and are now being sequenced in 400 additional familial cases. Reporting of the results of this work is eagerly awaited.DisclosuresNone.FootnotesCorrespondence to James F. Meschia, MD, Mayo Clinic, 4500 San Pablo Rd, Cannaday 2E, Jacksonville, FL 32224. E-mail [email protected]