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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The past several years have been marked by significant progress in identifying genetic anomalies in stroke-prone probands. These advances have occurred in both highly penetrant single-gene disorders and in common stroke, which is influenced by risk/susceptibility genes. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be challenging to diagnose because of the wide range of notch 3 mutations that can cause disease, but a new immunohistochemical technique using a skin biopsy sample appears to be highly sensitive and specific. In a landmark Icelandic study, linkage was established between stroke and a locus on chromosome 5q12 designated STRK1. Association studies continue to identify polymorphisms that predispose to stroke and to markers for cerebrovascular atherosclerosis, such as intima-media thickness. Intense interest now surrounds genes involved in inflammation, including genes that encode for the interleukin-1 receptor antagonist and paraoxonase-1. In the foreseeable future, prevention, diagnosis, and treatment will incorporate genetic data to refine and individualize management of cerebrovascular disease.
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PMID:New advances in identifying genetic anomalies in stroke-prone probands. 1279 73

The past several years have been marked by significant progress in identifying genetic anomalies in stroke-prone probands. These advances have occurred in both highly penetrant single-gene disorders and in common stroke, which is influenced by risk/susceptibility genes. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be challenging to diagnose because of the wide range of notch 3 mutations that can cause disease, but a new immunohistochemical technique using a skin biopsy sample appears to be highly sensitive and specific. In a landmark Icelandic study, linkage was established between stroke and a locus on chromosome 5q12 designated STRK1. Association studies continue to identify polymorphisms that predispose to stroke and to markers for cerebrovascular atherosclerosis, such as intima-media thickness. Intense interest now surrounds genes involved in inflammation, including genes that encode for the interleukin-1 receptor antagonist and paraoxonase-1. In the foreseeable future, prevention, diagnosis, and treatment will incorporate genetic data to refine and individualize management of cerebrovascular disease.
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PMID:New advances in identifying genetic anomalies in stroke-prone probands. 1532 9

Exciting advances have been made recently in genetic studies of coronary artery disease (CAD), myocardial infarction (MI), and ischemic stroke. One disease-causing gene for CAD and MI has been identified as MEF2A, which is located on chromosome 15q26.3 and encodes a transcriptional factor with a high level of expression in coronary endothelium. Approximately 1% to 2% of CAD patients may carry an MEF2A mutation. Four new susceptibility genes have been identified using genome-wide association studies or genome-wide linkage studies: LTA (encoding cytokine lymphotoxin-alpha) on 6p21.3 for MI; LGALS2 (encoding galectin-2, an LTA-interacting protein) on 22q12-q13 for MI; ALOX5AP (encoding 5-lipoxygenase activating protein involved in synthesizing potent pro-inflammatory leukotrienes) on 13q12-13 for MI and stroke; and PDE4D (encoding phosphodiesterase 4D) on 5q12 for ischemic stroke. These studies identify a new mechanism, the myocyte enhancer factor 2 (MEF2) signaling pathway of vascular endothelium, for the pathogenesis of CAD, and also confirm the role of inflammation in the disease process.
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PMID:Advances in the genetic basis of coronary artery disease. 1581 Dec 59

Genetic fine mapping of the first locus identified for genetically complex forms of stroke, STRK1 (which has been mapped to chromosome 5q12 in Icelandic families), has identified the phosphodiesterase 4D gene (PDE4D) gene as a good candidate gene. Association analysis of single nucleotide polymorphisms (SNPs) in the PDE4D gene in an Icelandic stroke cohort demonstrated genetic association between six SNPs in the 5' region of PDE4D and ischaemic stroke. The present study aimed to test whether the same six SNPs in PDE4D were also associated with stroke in a large stroke cohort from northern Germany (stroke patients with acute completed ischaemic stroke: n = 1181; population based controls: n = 1569). None of the six SNPs showed significant association with ischaemic stroke in the whole stroke sample before and after adjustment for conventional stroke risk factors (age, sex, hypertension, diabetes, and hypercholesterolaemia). Haplotype analysis did also not reveal any significant association. Marginally positive statistical measures of association in the subgroup with cardioembolic stroke did not remain significant after correction for multiple testing. In conclusion, this study was unable to demonstrate an association between the six SNPs which had showed significant single marker association with stroke in the Icelandic stroke cohort and ischaemic stroke in a large German cohort.
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PMID:Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort. 1654 35

There is increasing evidence that genetic factors are associated with ischemic stroke, including multiple recent reports of association with the gene PDE4D, encoding phosphodiesterase 4D, on chromosome 5q12. Genetic studies of stroke are important but can be logistically difficult to perform. This article reviews the design of the Siblings With Ischemic Stroke Study (SWISS) and discusses problems in performing a sibling-based pedigree study where proband-initiated consent is used to enroll pedigree members. Proband-initiated enrollment optimizes privacy protections for family members, but it is associated with a substantial pedigree non-completion rate such that 3 to 4 probands must be identified to obtain one completed sibling pedigree. This report updates the progress of enrollment in the SWISS protocol, discusses barriers to pedigree completion and describes innovative approaches used by the SWISS investigators to enhance enrollment.
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PMID:The Siblings With Ischemic Stroke Study (SWISS): a progress report. 1659 89

Biomarkers such as C-reactive protein (CRP) and myeloperoxidase (MPO) are elevated in patients with coronary artery disease and confer risk of acute cardiovascular events, such as myocardial infarction (MI) and stroke. More recently, variants in the 5-lipoxygenase-activating protein (FLAP) gene were shown to confer risk to both MI and stroke, effects that appear to be mediated through elevated LTB(4), a chemoattractant mediator shown to be upregulated in patients with MI. Another gene in the leukotriene (LT) pathway, LTA(4) hydrolase, was subsequently found to confer increased risk to MI, effects that were ethnicity-specific with an approximately threefold higher risk in African Americans than in whites. In another study, markers in the phosphodiesterase (PDE) 4D gene were found to confer risk to large-vessel occlusive and cardiogenic stroke. Interestingly, there is a cross-link between the 5-LO and the PDE4D pathways with converging biology. To address the role of an inhibitor of FLAP on biomarkers of MI risk, a randomized placebo-controlled phase II trial was conducted in patients with MI. This trial showed that LTB(4) and MPO production was reduced in whole blood leukocytes that were stimulated with ionomycin and the effects of the inhibitor were dose dependent. Serum CRP and plasma MPO were also reduced at the highest dose, which was well tolerated. These data suggest that LTB(4) is a risk factor of MI and that inhibition of FLAP and the LT pathway produces suppression of biomarkers that are associated with MI risk, including but not limited to LTB(4), MPO, and CRP, supporting the notion that the LTB(4) arm of the LT pathway may play a fundamental role in heart attacks and stroke.
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PMID:Role of FLAP and PDE4D in myocardial infarction and stroke: target discovery and future treatment options. 1663 37

Stroke can be viewed as a paradigm for late-onset, complex polygenic diseases. There are two main clinical phenotypes for stroke: ischemic stroke, responsible for 80-90% of stroke events, and hemorrhagic stroke, responsible for the remaining 10-20%. Stroke may either be the outcome of a number of monogenic disorders or, more commonly, a polygenic multifactorial disease. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the Notch 3 gene, is the best example of monogenic pathology leading to stroke. The identification of individual causative mutations for polygenic stroke is problematic due to the complexity of such condition. The two main methods of genetic investigation are linkage analyses and association studies, each with advantages and limitations. Associations with polymorphisms in a variety of candidate genes have been investigated, including hemostatic genes, genes controlling homocystein metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The combination of linkage and association approaches has led to the identification of the first putative gene associated with common polygenic stroke, PDE4D, mapped to chromosome 5q21. The biological revolution of the past years, spurred by the Human Genome Project, promises the advent of novel technologies supported by bioinformatics, which will transform the study of polygenic disorders such as stroke. Understanding the causes of stroke and its effect will allow definition of high-risk populations and make possible specific programs of primary and secondary prevention as well as new therapeutic approaches where prevention has failed.
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PMID:Research actuality in the genetics of stroke. 1683 24

Ischaemic stroke is a heterogeneous multifactorial disorder. Epidemiological data provide substantial evidence for a genetic component to the disease, but the extent of predisposition is unknown. Large progress has been made in single-gene disorders associated with ischaemic stroke. The identification of NOTCH3 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) has led to new insights on lacunar stroke and small-vessel disease. Studies of sickle-cell disease have drawn attention to the importance of modifier genes and of gene-gene interactions in determining stroke risk. They have further highlighted a potential role of genetics in predicting stroke risk. Little is known about the genes associated with complex multifactorial stroke. There are probably many alleles with small effect sizes. Genetic-association studies on a wide range of candidate pathways, such as the haemostatic and inflammatory system, homocysteine metabolism, and the renin-angiotensin aldosterone system, suggest a weak but significant effect for several at-risk alleles. Genome-wide linkage studies in extended pedigrees from Iceland led to the identification of PDE4D and ALOX5AP. Specific haplotypes in these genes have been shown to confer risk for ischaemic stroke in the Icelandic population, but their role in other populations is unclear. Advances in high-throughput genotyping and biostatistics have enabled new study designs, including genome-wide association studies. Their application to ischaemic stroke requires the collaborative efforts of multiple centres. This approach will contribute to the identification of additional genes, novel pathways, and eventually novel therapeutic approaches to ischaemic stroke.
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PMID:Genetics of ischaemic stroke. 1723 2

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.
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PMID:Advancing stroke therapeutics through genetic understanding. 1763 Sep 39

Sequence variations in genes involved in inflammation system are known to contribute to the risk of cardiovascular diseases (CVD) including stroke. In this study, we performed a genetic association study on the single nucleotide polymorphisms (SNPs) present in the genes CD14 (-159 C/T), TNFalpha (-308 G/A), IL-1alpha (-889 C/T), IL-6 (-174 G/C), PSMA6 (-8 C/G), and PDE4D (SNP83 T/C, respectively) in order to discern their possible role in the susceptibility to stroke in a North Indian population. These SNPs were previously found to be associated with CVD through their contribution to inflammation. A case-control design was used to examine 176 stroke patients (112 ischemic and 64 hemorrhagic stroke patients) and 212 unrelated healthy control individuals. After adjustment for the confounding risk factors, the IL-1alpha -889 T allele carriers (TT+CT) were found to be strongly associated with both forms of stroke (OR=2.56; 95% CI=1.53-4.29; P=0.0004). The CC genotype of PDE4D was found to be associated only with ischemic stroke (OR=2.02; 95% CI=1.08-3.76; P=0.03). None of the variants tested for the CD14, TNFalpha, IL-6, and PSMA6 genes found to confer risk for stroke in the study population. In conclusion, the -889 C/T and SNP83 T/C SNPs of the IL-1alpha and PDE4D genes, respectively, appear to be genetic risk factors for stroke in our study population.
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PMID:Inflammatory system gene polymorphism and the risk of stroke: a case-control study in an Indian population. 1815 10


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