Large Artery Atherosclerotic Ischemic Stroke Research Articles

Twenty-three medication-taking traits and stroke: A comprehensive Mendelian randomization study.

Certain medication categories may increase the risk of stroke. Nonetheless, the evidence regarding the causal relationship of medication-taking in promoting stroke and subtypes is deficient. We evaluated the causal effect of a genetic predisposition for certain medication categories on stroke and subtypes (ischemic and hemorrhagic categories) by a two-sample Mendelian randomization (MR) analysis. Data for 23 medication categories were gathered from a genome-wide association study (GWAS) involving 318,177 patients. The Medical Research Council Integrative Epidemiology Unit Open GWAS database and the FinnGen consortium were used to gather GWAS data for stroke and subtypes. Inverse variance weighted, MR-Egger, and weighted median were used for the estimation of causal effects. Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis were used for sensitivity analyses. Ten medication categories were linked to a high stroke risk. Nine categories were linked to a high-risk ischemic stroke. Five categories were associated with small vessel ischemic stroke. Nine categories were positively associated with large artery atherosclerotic ischemic stroke. Three categories causally increased the possibility of cardioembolic ischemic stroke. Four categories were associated with intracerebral hemorrhage. Four categories were associated with nontraumatic intracranial hemorrhage. Three categories were causally associated with subarachnoid hemorrhage (SAH). Four categories were associated with the combination of SAH, unruptured cerebral aneurysm, and aneurysm operations SAH. This study confirms that some medication categories lead to a greater risk of strokes. Meanwhile, it has an implication for stroke screening as well as direct clinical significance in the design of conduction of future randomized controlled trials.

Relationship between MTHFR C677T, homocysteine, and ischemic stroke in a large sample of the Han Chinese population.

Ischemic stroke, one of the prevalent causes of death and disability worldwide, is linked to environmental and genetic factors, including polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene involved in homocysteine metabolism. The present study aimed to explore the relationship between the MTHFR C677T variant, plasma homocysteine, and risk of developing large-artery atherosclerotic ischemic stroke (LAAIS) among Han Chinese.A population-based case-control study, which included 1810 patients with LAAIS and 1765 unrelated control subjects, was conducted. Compared to the controls, LAAIS patients had a significantly higher prevalence of hypertension, diabetes mellitus, smoking, and alcohol consumption (P < .001), as well as significantly higher mean fasting blood glucose, triglyceride, total cholesterol, and plasma homocysteine levels (P < .001). The TT homozygous genotype correlated with increased risk of developing LAAIS, as indicated by a significantly higher odds ratio (OR) compared to the CT and CC genotypes, in both additive (OR = 3.215, P = .01) and recessive models (OR = 3.265, P = .01). The plasma homocysteine level was genotype-dependent according to the following trend: TT > CT > CC.In conclusion, our data demonstrate that, in spite of its low prevalence in both patients and controls (1.5% vs 0.8%), the MTHFR C677T variant could, at least in part, affect homocysteine levels and this, either alone or in combination with other factors, increases the risk of LAAIS.

RNA sequencing uncover crucial genes mediating progression of large-artery atherosclerotic and small-artery occlusion ischemic stroke

PurposeThe goal of our study is to uncover the pathogenesis of large-artery atherosclerotic ischemic stroke (LAAIS) and small-artery occlusion ischemic stroke (SAOIS) and analyze their difference using RNA sequencing. MethodsRNA sequencing was used to filtrate differentially expressed mRNAs (DEmRNAs) and differentially expressed lncRNAs (DElncRNAs) in LAAIS and SAOIS. Specific DEmRNAs and DElncRNAs in LAAIS and SAOIS were further found. Functional annotation and DElncRNA-DEmRNA co-expression network were built to reveal biological function of DEmRNAs. ResultsA total of 832 DEmRNAs and 96 DElncRNAs were identified in LAAIS vs normal controls. 587 DEmRNAs and 105 DElncRNAs were identified in SAOIS vs normal controls. In LAAIS vs SAOIS, 636 DEmRNAs and 112 DElncRNAs were identified. Among which, 571 DEmRNAs and 61 DElncRNAs were LAAIS specific DEmRNAs and DElncRNAs, respectively. 325 DEmRNAs and 66 DElncRNAs were respectively SAOIS specific DEmRNAs and DElncRNAs. We also obtained 3086 LAAIS specific DElncRNA-DEmRNA co-expression pairs and 661 SAOIS specific DElncRNA-DEmRNA co-expression pairs. Oxidative phosphorylation and Alzheimer's disease were significantly enriched pathways in both LAAIS specific DEmRNAs and DEmRNAs in LAAIS specific DElncRNA-DEmRNA co-expression network. ECM-receptor interaction, hypertrophic cardiomyopathy and dilated cardiomyopathy were significantly enriched pathways in both SAOIS specific DEmRNAs and DEmRNAs in SAOIS specific DElncRNA-DEmRNA co-expression network. ConclusionThis finding may help to understand the mechanisms of LAAIS and SAOIS and offer novel clues for finding specific biomarkers for LAAIS and SAOIS.

TMAO as a Novel Predictor of Major Adverse Vascular Events and Recurrence in Patients with Large Artery Atherosclerotic Ischemic Stroke.

ObjectivesTo explore the association of plasma trimethylamine N-oxide (TMAO) concentration with large artery atherosclerotic (LAA) ischemic stroke and its role in predicting neurological outcome and major vascular event recurrence.Materials and MethodsWe performed a case-control study that included patients with first-ever LAA stroke as cases (n = 291) and asymptomatic patients as controls (n = 235). Clinical data and venous blood samples were collected within 72 hours after stroke. All subjects were followed for 3 months. TMAO level was detected by liquid chromatography mass spectrometry (LC-MS). Logistic and Cox proportional hazard regression were performed to evaluate plasma TMAO concentration as a predictor of LAA stroke and major vascular event recurrence, respectively. Kaplan–Meier survival analysis was performed to compare major vascular event recurrence between patients with high and low TMAO concentration.ResultsAfter adjusting for traditional stroke risk factors, the plasma TMAO level was significantly higher in the LAA stroke group than the control group (OR = 1.031, 95% CI 1.024-1.037, P < .001). At a cutoff level of 106.9 pg/ml, TMAO had a sensitivity of 63.23% and specificity of 80.00% in discriminating the LAA stroke subjects from the controls in Receiver operator characteristic (ROC) analysis. Kaplan–Meier survival analysis demonstrated TMAO plasma concentration was significantly relevant with recurrent vascular events (Log Rank, P = .006). Moreover, this association was still existed after adjusting for traditional risks (adjusted HR, 3.128; 95% CI, 1.018-9.610) in Cox regression model. But TMAO plasma levels were not relevant with functional disability after 3 months of the LAA stroke.ConclusionElevated plasma TMAO concentration was independently associated with LAA ischemic stroke. The risk of major vascular event recurrence increased by 2.128 times in the LAA stroke subjects with plasma TMAO level higher than 126.83 pg/mL. Plasma TMAO concentration might be a potential biomarker of major vascular event recurrence.

Missense Genetic Polymorphisms of Microsomal (EPHX1) and Soluble Epoxide Hydrolase (EPHX2) and Their Relation to the Risk of Large Artery Atherosclerotic Ischemic Stroke in a Turkish Population.

PurposeSoluble epoxide hydrolase (sEH) and microsomal epoxide hydrolase (mEH) both catalyze the metabolism of epoxyeicosatrienoic acids (EETs), lipid signaling molecules that are protective against ischemic brain injury owing to their participation in the regulation of vascular tone and cerebral blood flow. In addition, mEH metabolizes polycyclic aromatic hydrocarbons, one of the causative factors of atherosclerotic lesion development. In this study, we aimed to investigate the association of enzyme activity-modifying missense single nucleotide polymorphisms (SNPs) of the sEH gene (EPHX2) and mEH gene (EPHX1) and ischemic stroke risk in a Turkish population.Patients and MethodsGenomic DNA of patients with large artery atherosclerotic ischemic stroke (n=237) and controls (n=120) was isolated from blood samples, and genotypes for Tyr113His (rs1051740) and His139Arg (rs2234922) SNPs of EPHX1 and Arg287Gln (rs751141) SNP of EPHX2 were attained by the PCR/RFLP method.ResultsMinor allele frequency and genotype distributions for Arg287Gln, Tyr113His and His139Arg SNPs did not differ significantly between stroke patients and controls. However, hypertension- and diabetes-associated ischemic stroke risk was decreased by EPHX1 and increased by EPHX2 variants in stratification analyses.ConclusionThis study has shown for the first time that the polymorphic alleles of EPHX1 were unlikely to be associated with large artery atherosclerotic ischemic stroke susceptibility; however, protective effects were evident within subgroups of hypertension and diabetes. In addition, EPHX2 Arg287Gln polymorphism, which has been studied for the first time in a Turkish population, was not significantly related to ischemic stroke, but increased the stroke risk in subgroup analysis.

Association between lncRNA ANRIL genetic variants with the susceptibility to ischemic stroke: From a case-control study to meta-analysis.

Background:Recent studies have reported that lncRNA (long noncoding RNAs) antisense non-coding RNA in the INK4 locus (ANRIL) plays important roles in the development of atherosclerosis through regulating cell apoptosis, proliferation, and adhesion. GWAS (genome-wide association studies) identified common genetic variants within ANRIL could confer risk of ischemic stroke (IS) in southern Sweden.Methods:We performed a case-control study, including 567 IS patients and 552 healthy controls from unrelated northern Chinese Han population, aiming to explore the association between lncRNA ANRIL rs2383207, rs4977574 polymorphisms and the risk of IS. Subsequently we implemented a meta-analysis to further assess the relationship of these variants and the disease.Results:In our case-control study, no significant associations were observed in all models between above 2 polymorphisms and IS. Next in our subgroup analysis, we detected significant association between GA genotype of rs4977574 and the increased risk of LAA-IS (large-artery atherosclerotic ischemic stroke), similar elevated risk also appeared in the GG + GA genotype under the dominant model (P = .048, OR = 1.385, 95% CIs 1.002–1.914; P = .040, OR = 1.378, 95% CIs 1.015–1.872, respectively). As for rs2383207, negative results were obtained under all models and subgroups. Our meta-analysis showed a significant association between rs4977574 polymorphism and IS risk in allele model (G vs A P = .002, OR = 1.137, 95% CIs 1.048–1.234); with respect to rs2383207 polymorphism, no significant association between that and the risk of IS was detected under the dominant model (GA + AA vs GG, P = .061, OR = 0.923, 95% CIs 0.849–1.004), or recessive model (AA vs GA + GG, P = .656, OR = 0.972, 95% CIs 0.858–1.101), or allele model (A vs G, P = .326, OR = 0.952, 95% CIs 0.863–1.050). Likewise, no significant association between rs2383207 and IS was found in different stoke subtypes (P > .05).Conclusions:Our findings indicated G allele of lncRNA ANRIL rs4977574 could increase the risk of IS, and the variant may be associated with susceptibility to LAA-IS in Chinese Han population.

Low HDL-C levels are associated with cervicocerebral atherosclerotic stenosis in Southern Chinese patients with large artery atherosclerotic ischemic stroke

ObjectivesThe aim of this study is to investigate the association of HDL-C with CCAS, as well as its intracranial or extracranial location in the Southern Chinese population. Patients and methods123 Southern Chinese patients with large-artery atherosclerotic(LAA) ischemic stroke were enrolled for the final analysis. Based on the stenosis severity defined by digital subtraction angiography, the patients were categorized into CCAS and non-CCAS groups. The degree of artery stenosis among patients of CCAS was classified into three grades. CCAS were further categorized into intracranial AS (ICAS), Extracranial AS (ECAS) and combined intra-/extra-cranial AS (IECAS). ResultsIt was showed that patients with CCAS had a lower HDL-C level compared to NCCAS, and HDL-C levels were correlated to the degree of artery stenosis among CCAS. After adjusting for multiple potential confounders, low HDL-C level remained independently associated with CCAS(adjusted OR = 2.860). Patients with the lowest HDL-C quartile had a significantly increased risk for CCAS(adjusted OR: 5.771), referred to the highest quartile. But HDL-C levels in patients with ICAS, ECAS and IECAS were not significantly different, and there was no significant correlation between HDL-C levels and ICAS. ConclusionOur data indicate that low HDL-C level is associated with CCAS in Southern Chinese patients with LAA ischemic stroke. But the effects of HDL-C on the distribution of CCAS is required to be further explored.

Research progress of susceptibility genes associated with large artery atherosclerotic ischemic stroke

Research progress of susceptibility genes associated with large artery atherosclerotic ischemic stroke

GWAS-Supported CRP Gene Polymorphisms and Functional Outcome of Large Artery Atherosclerotic Stroke in Han Chinese.

Elevated C-reactive protein (CRP) levels increase the risk of poor functional disability in patients with ischemic stroke (IS). This study aimed to investigate the association between CRP gene polymorphisms and 3-month functional disability of large artery atherosclerotic (LAA) stroke in Han Chinese. Patients with first-ever LAA IS were prospectively enrolled in Nanjing Stroke Registry Program between August 2013 and October 2015. Five single-nucleotide polymorphisms (SNPs) (rs876537, rs2794520, rs3093059, rs7553007 and rs11265260) in CRP gene related to CRP levels in Asian by genome-wide association study were genotyped. The functional outcome at 3months after the index stroke was assessed by the modified Rankin scale. Associations between genotypes and functional outcome of LAA IS were analyzed with logistic regression model. A total of 690 eligible patients (507 males) were evaluated. SNPs rs11265260 (multivariate-adjusted, p = 0.022), rs2794520 (multivariate-adjusted, p = 0.036) and rs3093059 (multivariate-adjusted, p = 0.027) were significantly associated with elevated CRP in acute IS. Two SNPs, rs3093059 (dominant model: adjusted OR 2.49; 95% CI 1.55-4.00; recessive model: adjusted OR 3.67; 95% CI 1.22-11.03) and rs11265260 (dominant model: adjusted OR 2.51; 95% CI 1.56-4.02; recessive model: adjusted OR 4.70; 95% CI 1.63-13.56) independently predicted 3-month poor outcome of first-ever LAA IS, after adjusting for covariates. In addition, haplotype analysis indicated that haplotype GCTGC (adjusted OR 1.76; 95% CI 1.05-2.95; p = 0.031) increased the poor outcome risk. SNPs rs3093059 and rs11265260 in CRP gene may influence the 3-month functional outcome of first-ever LAA IS in Han Chinese.

Association of cytochrome P4502E1 and NAD(P)H:quinone oxidoreductase 1 genetic polymorphisms with susceptibility to large artery atherosclerotic ischemic stroke: a case-control study in the Turkish population.

Stroke, a major cause of death and disability, is described as interruption or severe reduction of blood flow in cerebral arteries. Oxidative stress plays an important role in the pathogenesis of atherosclerosis and carotid atherosclerosis is a risk factor for stroke. Combination of multiple environmental and genetic risk factors is thought to increase stroke. Therefore, investigation of the polymorphisms of enzymes is of crucial importance to determine the molecular etiology of the disease. To test this hypothesis, we performed a case-control study in which we compared the distribution of CYP2E1 and NQO1 genotypes between 245 large artery atherosclerotic ischemic stroke patients and 145 controls, using PCR-RFLP. A significant difference was observed between stroke patients and controls with respect to the CYP2E1*5B genotype (odds ratio; OR 8.069, P=0.011) and allele (OR 7.876, P=0.011) distribution. However, this polymorphism was not a significant predictor of disease status in logistic regression analysis. NQO1*2 polymorphism genotype distribution was significantly different between patients and controls (P=0.027) and heterozygote *1*2 genotype was found to be a protective factor against large artery atherosclerotic ischemic stroke in logistic regression analysis (OR 0.562, P=0.018). This is the first study conducted regarding the association of CYP2E1 and NQO1 genetic polymorphisms and large artery atherosclerotic ischemic stroke risk in Turkish population.

Soluble lectin-like oxidized low-density lipoprotein receptor-1 as a novel biomarker for large-artery atherosclerotic stroke

ABSTRACTBackground: Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been shown associated with the progression of atherosclerosis in endothelial cells. We sought to assess whether the baseline serum sLOX-1 levels are correlated with the presence and short-term functional outcome of large-artery atherosclerotic (LAA) stroke. Methods: The study recruited 241 subjects, including 148 consecutive patients with acute ischemic stroke with the subtype of LAA and 93 non-stroke controls. Clinical and laboratory data, including serum concentration of sLOX-1, were collected within 24 h of admission, and the severity of LAA stroke patients was evaluated by National Institutes of Health Stroke Scale score. And functional outcome was assessed by modified Rankin Scale three months after stroke. The association between sLOX-1 level and the functional outcome at three months was analyzed by multiple logistic regression models. Results: Serum levels of sLOX-1 in the LAA stroke patients were significantly higher as compared to normal controls (2.48 ± 0.93 ng/ml vs. 2.22 ± 0.79 ng/ml in the controls, t = 2.301, p = 0.022). The levels of serum sLOX-1 in patients with good outcome were significantly lower than those with poor outcome (2.39 ± 0.94 ng/ml vs. 2.77 ± 0.84 ng/ml, p = 0.032). After adjusting for potential confounders, sLOX-1 was still an independent predictor for the function outcome with an adjusted OR of 3.39 (95% CI, 1.61–7.11, p = 0.001). Conclusions: The serum sLOX-1 level was higher in patients with LAA stroke, and it was an independent predictor of functional outcome in patients with LAA ischemic stroke.

Abstract 13: A Locus on Chromosome 6p21 is Associated with Large Artery Atherosclerotic Ischemic Stroke

Introduction Genetic influences upon ischemic stroke risk are supported by the trait’s familial aggregation, higher concordance among monozygotic than dizygotic twins, and the high heritability of intermediate phenotypes such as carotid intima-media thickness. In spite of this evidence, genome-wide association studies (GWAS) have detected few replicable genetic risk factors for ischemic stroke, potentially due to aetiological heterogeneity of this trait. Hypothesis We first assessed the hypothesis that common ischemic stroke subtypes differ in their heritability, defined as the proportion of observed phenotypic variation attributable to genetic variation. The second hypothesis was that GWAS may detect stronger and more replicable genetic associations for distinct stroke subtypes with high heritability, rather than the broad ischemic stroke diagnosis. Methods An Australian, European-ancestry sample of 1230 ischemic stroke cases and 1280 population controls was genotyped for a genome wide association study using the Illumina 610-Quad array. Ischemic stroke subtypes were assigned using TOAST criteria. The proportion of case-control variation attributable to genome wide genetic variation was estimated using a published approach based on linear mixed models. Genome wide association analyses incorporating approximately 2.5 million genotyped and imputed SNPs were subsequently performed using a one-degree of freedom trend test assuming an additive effect of allele dosage. Results Significant evidence for a genetic contribution to ischemic stroke risk was detected ( h 2 =0.39, SE=0.15, p-value = 0.0009), but this was higher and more significant for the large artery atherosclerosis (LAA) subtype ( h 2 =0.66, SE=0.21, p-value = 0.0001). The genetic contributions to small vessel disease and cardioembolic stroke were less significant than for overall ischemic stroke. Genome wide association analyses including 421 LAA cases and 1244 controls detected a novel LAA susceptibility locus on chromosome 6p21.1 (two SNPs with P &lt;5×10 -8 ). The 6p21.1 locus showed markedly diminished association with the broader ischemic stroke phenotype. Conclusions In conclusion, this study detected higher heritability of large artery atherosclerotic stroke than cardioembolic stroke, small vessel disease or broad ischemic stroke. It suggests a genetic risk locus for large artery atherosclerosis on chromosome 6p21.1 and supports the analysis of aetiological subtypes to better identify genetic risk alleles for ischemic stroke.

Lack of evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke: A meta-analysis of 8,800 subjects

IntroductionEpidemiological studies have evaluated the association between factor XIII-A (FXIII-A) Val34Leu polymorphism and risk of ischemic stroke, but the results remain inconclusive. This meta-analysis was therefore designed to clarify these controversies. MethodsSystematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation (using the Newcastle-Ottawa Scale, NOS) were independently conducted in duplicate. Statistical analyses were performed using software Review Manager (Version 5.1.2) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by funnel plot, Egger's regression test and Begg's test. Sensitivity analysis was conducted by limiting the meta-analysis to the high quality studies (NOS score≥8). ResultsA total of 16 studies including 3,807 cases and 4,993 controls were combined showing no evidence of association between FXIII-A Val34Leu polymorphism and ischemic stroke (for Val/Leu vs. Val/Val : OR=0.95, 95%CI=0.77-1.16; for Leu/Leu vs. Val/Val: OR=0.90, 95%CI=0.73-1.11; for dominant model: OR=0.97, 95%CI=0.81-1.17; for recessive model: OR=0.95, 95%CI=0.77-1.17). In the subgroup analyses by study design, ethnicity and specific subtypes (small-vessel occlusive ischemic stroke and large-artery atherosclerotic ischemic stroke ), there was lack of evidence for the association. ConclusionsThis meta-analysis indicates that there is no evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke.