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

We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
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PMID:The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. 1477 Jan 84

Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases.
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PMID:Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. 1564 Sep 73

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

The quest for disease genes that confer risk for stroke is now being undertaken using three complementary approaches. Positional cloning using rare Mendelian phenocopies of stroke has found genes that contribute to rare forms of stroke but, so far, not to the common forms of stroke. Candidate-gene case-control association studies using the common forms of stroke have found suggestive associations of modest effect. However, positional cloning using hundreds of Icelandic families affected by the common forms of stroke has recently found two genes conferring substantial risk for ischemic stroke that have apparently been confirmed in the USA and other European populations. Both genes encode enzymes, phosphodiesterase 4D (PDE4D) and arachidonate 5-lipoxygenase-activating protein (FLAP), which suggest novel treatment strategies for stroke prevention.
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PMID:Genes contributing to risk for common forms of stroke. 1588 9

Risk for ischemic stroke is mediated by both environmental and genetic factors. Although several environmental exposures have been implicated, relatively little is known about the genetic basis of predisposition to this disease. Recent studies in Iceland identified risk polymorphisms in two putative candidate genes for ischemic stroke: phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP). A collection of North American sibling pairs concordant for ischemic stroke and two cohorts of prospectively ascertained North American ischemic stroke cases and control subjects were used for evaluation of PDE4D and ALOX5AP. Although no evidence supported linkage of ischemic stroke with either of the two candidate genes, single-nucleotide polymorphisms and haplotypic associations were observed between PDE4D and ischemic stroke. There was no evidence of association between variants of ALOX5AP and ischemic stroke. These data suggest that common variants in PDE4D may contribute to the genetic risk for ischemic stroke in multiple populations.
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PMID:Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. 1613 Jan 5

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

The 5-lipoxygenase activating protein, an important regulator in the biosynthesis of proinflammatory leukotrienes, has been reported to confer risks for cardiovascular diseases and stroke. The purpose of this study is to assess whether genetic variants in the ALOX5AP encoding the 5-lipoxygenase activating protein will influence the risk for stroke in the Chinese population. A total of 1,773 patients with stroke and 1,713 controls were recruited from seven clinical centers. Polymorphisms of SG13S114T/A and SG13S89G/A in the ALOX5AP were genotyped by the polymerase chain reaction and the restriction enzyme analysis. The multivariate logistic regression model was used to exclude the influence of the conventional vascular risk factors on stroke. The frequency of SG13S114A allele in the ALOX5AP was significantly higher in male patients with thrombotic stroke (33.6%) than in controls (29.2%; P=0.014). The SG13S114AA genotype was significantly associated with a 1.62-fold risk for thrombotic stroke in men (95% confidence interval, 1.11 to 2.35; P=0.012). The SG13S89G/A variant was not associated with stroke or its subtypes. Haplotype analysis showed no significant differences between stroke patients and controls. The present study suggested that a common genetic variant SG13S114T/A in the ALOX5AP gene is associated with an increased risk for atherothrombotic stroke in Chinese males, and racial differences in allele and genotype frequencies may account partially for the different association findings between populations.
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PMID:Polymorphism of SG13S114T/A in the ALOX5AP gene and the risk for stroke in a large Chinese cohort. 1693 1

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

Arachidonate 5-lipoxygenase activating protein (ALOX5AP) has been reported to demonstrate linkage and association with ischemic stroke and myocardial infarction. However, replication studies have been conflicting and to date, a significant proportion of blacks have not been studied. We prospectively recruited cases of ischemic stroke from all 16 hospitals in the Greater Cincinnati/Northern Kentucky region and demographically matched them to stroke-free population-based controls. Single nucleotide polymorphisms (SNPs) were selected based on association with ischemic stroke in prior studies. Allelic, genotypic and haplotypic association testing was performed using HAPLOVIEW. Multiple logistic regression was used to control for the presence of traditional risk factors including hypertension, diabetes, hypercholesterolemia and smoking. A total of 357 cases and 482 controls were genotyped. The SNPs, rs9579646 and rs4769874 were found to be significantly associated at both allelic (P=0.019 and P<10(-4), respectively) and genotypic level with ischemic stroke among whites after correction for multiple testing. Haplotype association was identified with ischemic stroke as well as ischemic stroke subtypes among whites. Although an overall haplotype association with ischemic stroke was identified among blacks no evidence of association among individual haplotypes, alleles or genotypes were observed. Allele frequencies for the SNPs examined were markedly different among whites and blacks. In conclusion, we report significant association of variants of ALOX5AP with ischemic stroke and ischemic stroke subtypes among whites. No significant association was identified among blacks.
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PMID:Association of ALOX5AP with ischemic stroke: a population-based case-control study. 1738 18

Stroke is a polygenic or multifactorial disease, and each single susceptibility gene has modest effects. We hypothesize that combined effects of multiple genes might confer a higher stroke risk than a single susceptibility gene. To test our hypothesis we initially recruited 2000 stroke patients (44.3% thrombosis, 28.3% lacunar infarction and 27.4% intracerebral hemorrhage) and 2000 controls, and examined 6 polymorphisms in 5 candidate genes for stroke. Plasma lipoprotein(a) [Lp(a)] level was defined as a categorical variable and also included. Interactions between genetic risk factors were detected by the multifactor dimensionality reduction (MDR) method and further evaluated by multivariate logistic regression analyses. A significant combined effect on stroke due to the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR), the T2354A polymorphism of 5-lipoxygenase activating protein (ALOX5AP), and Lp(a) level, was detected using the MDR method. Furthermore, the combination of MTHFR 677TT, ALOX5AP 2354AA and Lp(a) elevation (Lp(a) concentration > or = 30 mg/dL) was found to be strongly associated with thrombotic stroke in males (OR, 10.419; 95%CI, 2.602 to 41.749; P= 0.001) using the multivariate logistic regression model. In conclusion, our results show that a combination of genetic risk factors can confer a higher risk for stroke than a single risk factor, indicating that people with multiple genetic risk factors have a higher risk of stroke and should be targets for prevention of this disease.
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PMID:Interaction of genetic risk factors confers higher risk for thrombotic stroke in male Chinese: a multicenter case-control study. 1752 9


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