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

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

Leukotrienes have physiological roles in innate immune responses and pathological roles in inflammatory diseases, such as asthma, allergic rhinitis and atherosclerosis. Anti-leukotriene therapy has proven benefits in the treatment of respiratory disease, either through the inhibition of leukotriene synthesis or the selective antagonism of leukotriene receptors. The first committed step in the synthesis of leukotrienes is the oxidation of arachidonic acid (AA) by 5-lipoxygenase (5-LO), and the integral membrane protein 5-lipoxygenase-activating protein (FLAP) is an essential partner of 5-LO for this process. FLAP was molecularly identified via a photoaffinity probe and an affinity gel based on MK-886, a selective leukotriene inhibitor that has no activity against broken-cell preparations of 5-LO. Several FLAP inhibitors showed efficacy in early clinical trials in asthma but were not developed commercially for unpublished reasons. Recently, the FLAP (ALOX5AP) gene has been linked to risk for myocardial infarction, stroke and restenosis, reigniting pharmaceutical interest in this target. In addition, the recent determination of the crystal structure of inhibitor-bound FLAP offers exciting potential for novel FLAP inhibitor design.
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PMID:What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases. 1818 10

Genetic variation in the genes ALOX5AP (arachidonate 5-lipoxygenase-activating protein) and LTA4H (leukotriene A4 hydrolase) has previously been shown to contribute to the risk of MI (myocardial infarction) and stroke in Icelandic and Scottish populations. Both genes encode proteins playing a role in the synthesis of the pro-inflammatory leukotriene B mediators, possibly providing a link between MI and inflammation. The aim of the present study was to investigate whether these associations could be confirmed in a large study of German MI patients. Two previously described four SNP (single nucleotide polymorphism) haplotypes of the ALOX5AP gene (termed haplotype A and B) and one SNP (rs2660899) of the LTA4H gene conferring the greatest risk of MI in previous studies were genotyped in 1211 unrelated MI cases from the German MI Family Study and in 1015 healthy married-in spouses serving as controls. Haplotype B in the ALOX5AP gene was associated with an increased risk of MI in the German population, confirming previously reported associations of this haplotype with CAD (coronary artery disease) in populations from Scotland and Italy. No association with the risk of MI was detected for haplotype A of the ALOX5AP gene or for SNP rs2660899 representing the LTA4H gene. In conclusion, haplotype B of the ALOX5AP gene is associated with an increased risk of MI in a large German study. The present study is the third independent report from a European population describing an increased risk of CAD for carriers of haplotype B of the ALOX5AP gene, which substantiates further a role of this gene in the pathogenesis of CAD in Europeans.
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PMID:Genetic variation in the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) is associated with myocardial infarction in the German population. 1831 62

Previous Icelandic studies reported that single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) region and the 5-lipoxygenase activating protein ALOX5AP were associated with ischaemic stroke, whereas other studies reported ambiguous findings. We examined 932 ischaemic stroke patients from a Swedish population-based stroke register, and 396 control subjects. We assessed possible associations between ischaemic stroke and nine preselected SNPs in the chromosome regions of the PDE4D gene, including rs12188950 (SNP45) and rs3887175 (SNP39); the ALOX5AP gene, including rs17222814 (SG13S25) and the promoter region of the MHC class II transactivator, MHC2TA. The T allele of SNP45 showed negative association with ischaemic stroke (odds ratio, OR=0.72; 95% confidence interval (CI): 0.58-0.91; P=0.0055). Among hypertensive subjects, this influence of the T allele of SNP45, and the T allele of SNP39, were more pronounced (with OR=0.52; 95% CI: 0.37-0.73; P=0.0001 and OR=0.57; 95% CI: 0.41-0.79; P=0.0007, respectively). These SNPs also interacted with hypertension with a relative excess risk due to interaction of -1.66 (P=0.0002) for SNP45 and -1.65 (P=0.0005) for SNP39. The P-values remained significant after correction for multiple testing. Among nonhypertensives, the A allele of SG13S25 indicated increased stroke risk (OR=1.82; 95% CI: 1.21-2.74; P=0.0039; not significant after Bonferroni correction). SNP45 was associated with ischaemic stroke even when controlling for hypertension, diabetes, heart disease and smoking. Our meta-analysis of 13 studies (including ours) showed no overall influence of SNP45 on ischaemic stroke. However, the 13 studies may differ because of nonrandom causes, as suggested by the heterogeneity test (P=0.042). This might support previously undetected mechanisms causing fluctuating ischaemic stroke risk.
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PMID:Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region. 1839 40

Single-gene disorders explain only a minority of stroke cases. Stroke represents a complex trait, which is usually assumed to be polygenic. On this topic, the role of a wide number of candidate genes has been investigated in stroke through association studies, with controversial results. Therefore, it is difficult for the clinician to establish the validity and the level of clinical applicability of the previously reported associations between genetic factors and stroke. This review is an update and an extensive analysis of the more recent association studies conducted in stroke. We evaluated a number of studies on several candidate genes (including F5, F2, FGA/FGB/FGG, F7, F13A1, vWF, F12, SERPINE1, ITGB3/PLA1/PLA2/ITGA2B, ITGA2, GP1BA, ACE, AGT, NOS3, APOE, LPL, PON1, PDE4D, ALOX5AP, MTHFR, MTR, and CBS), providing a final panel of genes and molecular variants. We categorized this panel in relation to the degree of association with stroke, supported by the results of meta-analyses and case-control studies. Our findings could represent a useful tool to address further molecular investigations and to realize more detailed meta-analyses.
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PMID:Genetic polymorphisms for the study of multifactorial stroke. 1842 1

Stroke is a multifactorial disease responsible for nearly 10% of deaths each year in industrialized countries. While some monogenic forms of stroke have been described, the vast majority result from the common polygenic form of the disease. Progress in molecular genetics has allowed the identification, through genome-wide linkage analysis, of various candidate genes, including the genes encoding PDE4D and ALOX5AP. Since then, genetic research has been extensively performed from single candidate genes to whole-genome scan studies, in parallel with the development of high-throughput technologies in molecular diagnostics. Additionally, the safety and efficacy of tissue plasminogen activator, the only approved therapy for the acute phase of stroke, is modulated by genetic background associated with the occurrence of hemorrhagic transformations and with the revascularization of the cerebral arteries. In the near future, understanding the contribution of stroke genetic factors will lead to improvements in prevention and treatments for neurovascular diseases.
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PMID:Genetics of stroke: a review of recent advances. 1859 30

Despite recent advances in acute stroke therapy, stroke remains the leading cause of severe disability and the third leading cause of death, after heart disease and cancer, in Western countries and Japan. The identification of biomarkers of stroke risk is thus important both for risk prediction and for intervention to avert future events. Although genetic linkage analyses of families and sib-pairs as well as candidate gene and genome-wide association studies have implicated several loci and candidate genes in predisposition to ischemic or hemorrhagic stroke, the genes that contribute to genetic susceptibility to these conditions remain to be identified definitively. Given that vascular inflammation has been recognized as an important mechanism of atherosclerotic disease, proinflammatory genes may play pivotal roles in the pathogenesis of ischemic stroke. In this review, we summarize candidate genes that have been implicated in common forms of ischemic stroke by linkage analyses and association studies. We also review in more detail studies that have revealed an association of ischemic stroke with polymorphisms of proinflammatory genes of particular interest (LTA, IL6, and ALOX5AP) as well as with polymorphisms at chromosomal region 9p21.3, which has recently been identified as a susceptibility locus for coronary heart disease. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of ischemic stroke.
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PMID:Proinflammatory gene polymorphisms and ischemic stroke. 1907 35

Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene have been implicated as a risk factor for stroke. However, genetic association studies that have examined the association between ALOX5AP gene variants (HapA haplotype, HapB haplotype, and SG polymorphisms) and stroke have produced conflicting results. Therefore, the authors performed a meta-analysis of all studies with ALOX5AP genotyping (5,194 stroke cases and 4,566 controls). The meta-analysis showed significant heterogeneity among studies (P(Q) = 0.03, I(2) = 63%) and a nonsignificant association between the HapA haplotype (SG13S25G-SG13S114T-SG13S89G-SG13S32A) and stroke risk (random-effects (RE) odds ratio (OR) = 1.13, 95% confidence interval (CI): 0.88, 1.45). Regarding the HapB haplotype (SG13S377A-SG13S114A-SG13S41A-SG13S35G), there was no association with stroke risk (RE OR = 1.03, 95% CI: 0.77, 1.37). The SG13S114, SG13S89, SG13S25, SG13S32, SG13S35, and SG13S42 polymorphisms were not associated with stroke. The SG13S106 and SG13S377 polymorphisms revealed evidence of marginal association (RE OR = 1.23 (95% CI: 1.03, 1.46) and RE OR = 1.25 (95% CI: 1.04, 1.50), respectively). However, cumulative meta-analysis for the HapA haplotype showed a downward trend of odds ratios over time, and recursive cumulative meta-analysis indicated insufficient evidence for claiming or denying an association. Tests for bias revealed no evidence of biases. Rigorous genetic association studies investigating gene-gene-environment interactions may generate more conclusive claims about the genetics of stroke.
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PMID:Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of stroke: a HuGE gene-disease association review and meta-analysis. 1912 81

Stroke is a common complex trait and does not follow Mendelian pattern of inheritance. Gene-gene or gene-environment interactions may be responsible for the complex trait. How the interactions contribute to stroke is still under research. This study aimed to explore the association between gene-gene interactions and stroke in Chinese in a large case-control study. Nearly 4,000 participants were recruited from seven clinical centers. Eight variants in five candidate genes were examined for stroke risk. Gene-gene interactions were explored by using Generalized Multifactor Dimensionality Reduction (GMDR). A significant gene-gene interaction was found by GMDR. The best model including MTHFR C677T, ALOX5AP T2354A and NOTCH3 C381T scored 10 for Cross-Validation Consistency and 9 for Sign Test (P = 0.0107). The individuals with combination of MTHFR 677TT, ALOX5AP 2354AA and NOTCH3 381TT/TC had a significantly higher risk of thrombotic stroke (OR 3.165, 95% CI 1.461-6.858, P = 0.003). Our results show that combination of these alleles conferred higher risk for stroke than single risk allele. The gene-gene interaction may serve as a novel area for stroke research. The three-locus combination may change the susceptibility of particular subjects to the disease.
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PMID:Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case-control study. 1937 90

Genetic factors contribute to the risk of ischemic stroke (IS). The phosphodiesterase-4D (PDE4D) and the 5-lipoxygenase activating protein (ALOX5AP) genes were identified as contributors to stroke in an Icelandic population. In an attempt to better define the contributory role of PDE4D and ALOX5AP genes to the risk of IS in humans, we carried out the present association study in a well-characterized, earlier published, genetically homogenous population from the island of Sardinia, Italy. In this cohort, including 294 cases and 235 controls, age, hypertension, hypercholesterolemia, and atrial fibrillation represent risk factors for IS. The PDE4D gene was evaluated by four single nucleotide polymorphisms (SNP32, SNP45, SNP83, SNP87) and by the microsatellite AC008818-1; the ALOX5AP gene was characterized by three SNPs (SG13S32, SG13S89, ALO2A). The results of our study provide no evidence of association between any single PDE4D and ALOX5AP gene variant with the risk of IS in the Sardinian cohort. Haplotype analysis, including that constructed with allele 0 of microsatellite AC008818-1 and SNP45 of the PDE4D gene, was also negative. In conclusion, we found no evidence of association between PDE4D and ALOX5AP genes and the risk of IS in a genetically homogenous population from Sardinia.
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PMID:Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians. 1941 66


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