Factors associated with clopidogrel resistance and clinical outcomes in ischemic cerebrovascular disease: A retrospective study.

OBJECTIVE: Clopidogrel resistance may lead to the recurrence of cerebrovascular diseases. We aimed to identify potential factors associated with clopidogrel resistance and evaluate the clinical outcomes of the patients. MATERIALS AND METHODS: In this retrospective study, patients with ischemic cerebrovascular disease treated with clopidogrel were included and classified into 2 groups according to the adenosine diphosphate (ADP)-induced platelet aggregation. Patients with the ADP inhibition rate of <30 % were included in clopidogrel resistance group, otherwise were included in clopidogrel sensitive group. CYP2C19 genotype and other clinical data were analyzed to identify factors and clinical features in the multivariate analysis. The outcomes were vascular events in 6 months. RESULTS: In total, 139 patients were enrolled with 81 (58.27 %) in clopidogrel sensitive group and 58 (41.73 %) in clopidogrel resistance group. Female and CYP2C19 *2*3 carrying were risk factors for clopidogrel resistance, and female was an independent risk factor (OR 2.481, 95 % CI 1.066-5.771, P=0.035). The clopidogrel resistance group showed a higher use rate of argatroban (P=0.030) and a lower arachidonic acid-induced inhibition of platelet aggregation (P=0.036). Clopidogrel resistance was related to the progressing stroke (HR 3.521, 95 % CI 1.352-9.170, P=0.010), but had no influence on the bleeding events (P>0.05). CONCLUSIONS: The risk of clopidogrel resistance increased significantly in female patients. Patients with clopidogrel resistance may have an increased incidence of stroke progression in the acute phase.

Genetic correlations and causal inferences in ischemic stroke.

BACKGROUND AND PURPOSE: Considerable studies have reported inconsistent relationships between ischemic stroke and a large number of factors. These uncertainties may reflect the susceptibility to confounding in observational studies. We aimed to assess genetic correlations and causal relationships between ischemic stroke and diverse phenotypes. METHODS: Summary-level data for ischemic stroke (34,217 cases and 406,111 controls) from the MEGASTROKE consortium were used as the outcome. Exposures were derived from two GWAS statistics curated databases. We explored the genetic correlations and causalities between hundreds of traits and ischemic stroke, using linkage disequilibrium score regression and Mendelian randomization (MR), respectively. Multiple sensitivity analyses were also performed. RESULTS: Genetic correlation analyses reflected genetic overlaps between ischemic stroke and physical activity, cardiometabolic factors, smoking, and lung function. Applying MR, we found suggestive evidence that genetic predisposition to higher concentration of low-density lipoprotein particles (LDL.P) and cholesterol carried in different sizes of LDL.P (LDL.C) were associated with higher risk of ischemic stroke, particular large artery stroke. The strongest effect was observed for small LDL.P in large artery stroke (OR 1.31, 95% CI 1.09-1.56, p = 0.003). The results were overall robust for sensitivity analyses. We further observed significant positive associations of genetically predicted LDL.P and LDL.C with coronary artery disease and myocardial infarction. CONCLUSIONS: Shared genetic overlaps might exist between ischemic stroke and physical activity, cardiometabolic factors, smoking, and lung function. We provided suggestive evidence for a potential causal role of LDL.P and LDL.C in ischemic stroke, particularly in large artery stroke. Future researches are required to confirm these findings.

Major depression and small vessel stroke: a Mendelian randomization analysis.

BACKGROUND AND PURPOSE: Although observational studies have reported a positive association between depression and ischemic stroke, causality remains inconclusive. We aimed to assess the causal relationship of major depressive disorder (MDD) with ischemic stroke, especially with the small vessel stroke (SVS) subtype. METHODS: We used 72 independent single-nucleotide polymorphisms associated with MDD in a genome-wide association study (GWAS) from the Psychiatric Genetics Consortium as instrumental variables. The corresponding data for ischemic stroke and its subtypes of European ancestry were available from the MEGASTROKE consortium of 34,217 ischemic stroke cases and 406,111 controls. Primary Mendelian randomization estimates were calculated with inverse-variance weighted method, and several alternate methods and multiple sensitivity analyses were also performed. RESULTS: We found that genetic predisposition to higher risk of MDD was associated with higher risk of SVS, with an odds ratio of 1.33 (95% confidence interval, 1.08-1.65; p = 0.009) per log-odds increment in MDD risk, but not with large artery stroke (OR, 1.08; 95% CI 0.83-1.41; p = 0.559), cardioembolic stroke (OR, 0.98; 95% CI 0.80-1.20; p = 0.833), or all ischemic stroke (OR, 1.03; 95% CI 0.92-1.15; p = 0.633). The association of MDD with SVS was overall robust to sensitivity analyses. CONCLUSIONS: We provided evidence for a possible causal effect of MDD on increased risk of SVS. Future researches are required to investigate whether rational intervention on depression may help to reduce societal burden of SVS.

Chromosome 10q25 polymorphism is associated with susceptibility to large artery atherosclerotic stroke.

BACKGROUND AND AIMS: A recent genome-wide association study (GWAS) reported an association between a single nucleotide polymorphism (SNP) rs11196288 and risk of early-onset large artery atherosclerotic (LAA) stroke in European population. The interaction between genetic and environmental factors such as age has also received increasing attention. We performed this study to investigate the association between the rs11196288A > G polymorphism and LAA stroke risk in the Chinese Han population and test whether age interacts rs11196288 to influence LAA stroke risk. METHODS: Genotyping of rs11196288 was performed in 1066 LAA stroke patients and 1167 healthy controls. Multivariate logistic regression analyses were applied to assess the effect of the rs11196288A > G polymorphism on susceptibility and short-term outcome of LAA stroke. Nomograms were performed to estimate probability of risk for an individual patient. RESULTS: A significant decrement of LAA stroke risk was found in co-dominant (AG vs. AA, OR = 0.76, 95% CI = 0.64-0.91, P = 0.003; GG vs. AA, OR = 0.65, 95% CI = 0.50-0.85, P = 0.002), dominant (AG/GG vs. AA, OR = 0.74, 95% CI = 0.62-0.87, P < 0.001) and recessive models (GG vs. AA/AG, OR = 0.76, 95% CI = 0.59-0.97, P = 0.028) of rs11196288. However, the interaction between age and genotypes of rs11196288 was not statistically significant, and no significant association was observed between the rs11196288A > G polymorphism and short-term outcome of LAA stroke (P > 0.05). CONCLUSIONS: In the southeastern Chinese population, the rs11196288A > G polymorphism is associated with decreased risk of LAA stroke.

Premorbid dietary intake of protein is associated with early outcomes but not with severity of ischemic stroke.

BACKGROUND AND OBJECTIVES: Dietary protein intake has been associated with reduced risk of stroke. This study aimed to examine the relationship between premorbid dietary intake of protein and both stroke severity and neurological outcomes in patients with acute ischemic stroke. METHODS AND STUDY DESIGN: Consecutive patients with first-ever ischemic stroke in Jinling Hospital were screened for eligibility of participation. A validated foodfrequency questionnaire (FFQ) was performed to collect necessary data for calculating pre-stroke dietary intakes. Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) at baseline. Neurological outcomes were assessed by the modified Rankin scale (mRS) 90 days after stroke onset. Multivariable logistical regression was applied to analyze the impacts of dietary protein intake on stroke severity or neurological outcomes. RESULTS: Of the 201 enrolled patients, 110 (54.7%) were classified as minor (NIHSS ≤5) and 91 (45.3%) as major stroke (NIHSS ≥6). After adjusting for potential confounders, multivariable logistic regression did not detect significant association between total (odds ratio (OR)=0.98, p=0.15), animal (OR=1.01, p=0.87) or plant protein intake (OR=0.96, p=0.07) and stroke severity. According to the 90-day mRS, 127 patients (63.2%) were determined with good (mRS ≤2), and 74 (36.8%) with poor outcomes (mR 3-6). Multivariable logistic regression detected that premorbid dietary intake of total protein was positively associated with good neurological outcomes (OR=1.05, p=0.04). CONCLUSIONS: Higher level of premorbid protein intake may be associated with favorable neurological outcomes independent of stroke severity.

Association between PTGS1 polymorphisms and functional outcomes in Chinese patients with stroke during aspirin therapy: Interaction with smoking.

PURPOSE: Prostaglandin-Endoperoxide Synthase 1 (PTGS1) and smoking may play important roles in aspirin nonresponsiveness, but the effect of their interaction on stroke outcomes remains largely unknown. We examined the effects of PTGS1 polymorphisms, smoking status, and their interaction on functional outcomes in a cohort of Chinese Han patients with stroke during aspirin therapy. METHODS: A total of 617 ischemic stroke patients taking aspirin were enrolled. Three single nucleotide polymorphisms (SNPs) rs1330344, rs3842788, and rs5788 in PTGS1 were determined for genotyping. Poor functional outcomes were defined as a modified Rankin Scale (mRS) of 3-6 at 90-day follow-up. The influence of PTGS1 gene-smoking interaction on functional outcomes was examined. RESULTS: Poor functional outcomes occurred in 145 (23.5%) patients. When adjusting multiple factors by logistic regression, CC genotype of rs1330344 was associated with poor functional outcomes (risk ratio [RR]=1.73; 95% confidence interval [CI]: 1.17-2.37). A similar connection was found in the CGC haplotype (RR=1.40; 95% CI: 1.08-1.77). Furthermore, we found a significant interaction between rs1330344 and smoking status (Pinteraction=0.018); the interaction effect between the PTGS1 haplotype and smoking also showed statistical significance (Pinteraction=0.040). CONCLUSIONS: In Chinese Han stroke patients with aspirin therapy, the adverse effect of PTGS1 polymorphisms on functional outcomes may be modulated by the smoking status. PTGS1 gene-smoking interaction might in part reflect the heterogeneity in the prognosis of patients treated with aspirin.

The Relationship between Neutrophil-to-Lymphocyte Ratio and Aortic Arch Calcification in Ischemic Stroke Patients.

BACKGROUND: Inflammation plays a central role in atherogenesis and artery calcification. Although neutrophil-to-lymphocyte ratio (NLR) has been introduced as an inflammatory marker for atherosclerosis, the relationship between NLR and aortic arch calcification (AAC) has not been studied. This study aimed to determine the association between NLR and AAC. METHODS: A total of 749 participants were enrolled. Demographic and clinical data were collected. Degree of AAC in each enrolled patient was determined with Agatston method based on a neck computed tomography angiography. NLR was divided into 4 groups according to quartile values. Generalized linear model (ordinal probit) was performed to assess the association between NLR quartiles and severity of AAC. RESULTS: There were 151 (20.2%), 153 (20.4%), and 445 (59.4%) patients classified as without AAC, with mild AAC, and with severe AAC, respectively. Patients with severe AAC had the highest NLR values (2.37[1.79-3.42] versus 2.29[1.55-2.96] versus 2.17[1.64-2.91], P = .025) compared to patients without AAC and with mild AAC. In age- and sex-adjusted models, patients with the highest NLR (quartile 4) were correlated with severer AAC (ß = .348 ± .128, P = .006) compared to those with the lowest levels (quartile 1). The correlation between NLR quartile 4 and severer AAC still existed (ß = .335 ± .129, P = .009) in multivariable-adjusted model. CONCLUSIONS: This study suggested that NLR may reflect the severity of AAC. NLR may be considered as a valuable predictor of the degree of artery calcification.

CDKN2B Methylation and Aortic Arch Calcification in Patients with Ischemic Stroke.

AIM: CDKN2A/2B near chromosome 9p21 has been proposed as a potential genetic etiology for both atherosclerosis and arterial calcification. DNA methylation, which can change the expression of CDKN2A/2B, may be an underlying mechanism for this association. This study aimed to evaluate whether CDKN2A/2B methylation is related to aortic arch calcification (AAC) in patients with ischemic stroke. METHODS: DNA methylation levels of CDKN2A/2B was measured using venous blood samples in 322 patients with ischemic stroke. A total of 36 CpG sites around promoter regions of CDKN2A/2B were examined. AAC was quantified with Agatston score based on results of computed tomography angiography. RESULTS: There were 248 (77.0%) patients with and 74 (23.0%) patients without evident AAC. Compared with patients without AAC, patients with AAC had higher methylation levels of CDKN2B (5.72 vs 4.94, P＜0.001). Using a generalized linear model, positive correlation between methylation levels and log-transformed calcification scores was detected at CDKN2B (ß=0.275±0.116, P= 0.018). CONCLUSION: Patients with higher levels of DNA methylation of CDKN2B may bear increased risk for AAC. Further studies to reveal the underlying mechanisms of this association are warranted for establishing a cause-effect relationship.

Fine-Mapping of ABO Gene Identifies Two Novel SNPs Associated with Large Artery Atherosclerotic Stroke in a Chinese Han Population.

Recently, a single nucleotide polymorphism (SNP) rs505922 in ABO gene was related to large artery atherosclerotic (LAA) stroke in Caucasian populations by genome-wide association study (GWAS). This study aimed to determine whether ABO gene polymorphisms are associated with LAA stroke in Chinese Han population. A case-control study was designed, and 644 patients with LAA stroke and 642 healthy controls were enrolled. Ten tagging SNPs (tSNPs) located in ABO gene were genotyped. Associations between genotypes and LAA stroke were analyzed with logistic regression model after adjustment of potential confounders. Although rs505922 was not associated with LAA stroke (TT genotype, adjusted OR = 1.32; 95 % CI, 0.94 to 1.87), two novel SNPs, rs8176668 (AT genotype, adjusted OR = 0.71; 95 % CI, 0.55 to 0.92) and rs2073824 (AA genotype, adjusted OR = 0.72; 95 % CI, 0.57 to 0.92), were associated with LAA stroke. Haplotype analysis indicated that haplotype TC (adjusted OR = 0.72; 95 % CI, 0.54 to 0.95; P = 0.018) in block 1 and haplotype ACA in block 2 (OR = 0.73; 95 % CI, 0.58 to 0.91; P = 0.005) were associated with LAA stroke. Multifactor dimensionality reduction (MDR) analysis in the single-locus model indicated that rs2073824 was the most important attributor for predicting risk of LAA stroke. No significant SNP-SNP interactions among the tested SNPs were detected. The results indicated that the genetic variants in ABO gene may influence the risk of LAA stroke in Chinese Han population.

Genetic Variants in MicroRNAs Predict Recurrence of Ischemic Stroke.

MicroRNAs are a recently discovered class of small noncoding RNA, which play key roles in every aspect of brain function, including neural development and neurogenesis. Since abnormal expression and function of microRNAs has been observed in ischemic stroke, we evaluated whether genetic variations in microRNAs can influence the clinical behavior of ischemic stroke. Common functional microRNA SNPs (i.e., miR-146a rs2910164, miR-149 rs2292832, miR-196a2 rs11614913, miR-499 rs3746444, miR-605 rs2043556, and miR-618 rs2682818) were genotyped in 914 patients with ischemic stroke. MicroRNAs variants were not associated with age of ischemic stroke onset (P > 0.05). However, we found that miR-618 rs2682818 GT/TT genotypes were significantly associated with an increased risk of ischemic stroke recurrence, compared with the GG genotype (hazard ratio [HR] = 1.72; 95 % confidential interval [CI], 1.08 to 2.74; log-rank P = 0.006), and this effect was more pronounced among subjects with small-vessel disease (HR = 2.60; 95 % CI, 1.11 to 6.08; log-rank P = 0.007). Moreover, the variant genotypes (GT/TT) of rs2682818 were an independent prognostic factor for ischemic stroke in the multivariate Cox regression model. Our findings suggest that miR-618 SNP rs2682818 may play an important role in the recurrence of ischemic stroke.

Association of GWAS-Supported Variants rs556621 on Chromosome 6p21.1 with Large Artery Atherosclerotic Stroke in a Southern Chinese Han Population.

Recent genome-wide association study associated rs556621 on chromosome 6p21.1 with the risk of large artery atherosclerotic (LAA) stroke in Caucasians. However, subsequent replicate studies showed conflict results in different ethnicities. This study aimed to evaluate whether rs556621 was associated with LAA stroke in Chinese Han population. In this case-control study, 659 patients with LAA stroke and 650 healthy controls were enrolled. Associations between rs556621 genotypes and LAA stroke were analyzed with logistic regression model. Rs556621 variants were associated with increased risks of LAA stroke (codominant model: OR 1.42; 95 % CI 1.01-1.99; P = 0.010; recessive model: OR 1.40; 95 % CI 1.05-1.86; P = 0.003). When subjects were stratified by sex, TT genotype of SNP rs556621 was associated with an increased risk of LAA stroke in female when tested with recessive model (OR 2.36; 95 % CI 1.28-4.36, P = 0.006). In male subjects, however, no significant association was detected. Smoking status, sex did not significantly influence the relationship between genotypes of rs556621 and risk of LAA stroke (P interaction = 0.140, P interaction = 0.076). Rs556621 may play an important role in the development of LAA stroke in female Chinese of Han ethnicity. Larger studies with subjects of different ethnicities are warranted to confirm these findings.

CDKN2B methylation is associated with carotid artery calcification in ischemic stroke patients.

BACKGROUND: Cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) near chromosome 9p21 have been associated with both atherosclerosis and artery calcification, but the underlying mechanisms remained largely unknown. Considering that CDKN2A/2B is a frequently reported site for DNA methylation, this study aimed to evaluate whether carotid artery calcification (CarAC) is related to methylation levels of CDKN2A/2B in patients with ischemic stroke. METHODS: DNA methylation levels of CDKN2A/2B were measured in 322 ischemic stroke patients using peripheral blood leukocytes. Methylation levels of 36 CpG sites around promoter regions of CDKN2A/2B were examined with BiSulfite Amplicon Sequencing. CarAC was quantified with Agatston score based on results of computed tomography angiography. Generalized liner model was performed to explore the association between methylation levels and CarAC. RESULTS: Of the 322 analyzed patients, 187 (58.1%) were classified as with and 135 (41.9%) without evident CarAC. The average methylation levels of CDKN2B were higher in patents with CarAC than those without (5.7 vs 5.4, p = 0.001). After adjustment for potential confounders, methylation levels of CDKN2B were positively correlated with cube root transformed calcification scores (ß = 0.591 ± 0.172, p = 0.001) in generalized liner model. A positive correlation was also detected between average methylation levels of CDKN2B and cube root transformed calcium volumes (ß = 0.533 ± 0.160, p = 0.001). CONCLUSIONS: DNA methylation of CDKN2B may play a potential role in artery calcification.

The impacts of premorbid hypertension treatment on functional outcomes of ischemic stroke.

BACKGROUND AND PURPOSE: The low rate of hypertension control is a major cause for the high rate of stroke morbidity and mortality in China. This study aimed to evaluate the impacts of premorbid hypertension treatment on the functional outcomes in patients with acute ischemic stroke and hypertension. METHODS: Patients with first-ever ischemic stroke and hypertension were screened from Nanjing Stroke Registry Program for eligibility. Functional outcomes were followed at 3 months with modified Rankin Scale (mRS). A good functional outcome was defined as mRS≤2. Potential factors associated with good functional outcomes were analyzed with multivariate logistic regression. RESULTS: A total of 660 patients with both ischemic stroke and hypertension were included, of whom 284 (43.0%) were on antihypertensives before stroke. In univariate analysis, more patients with hypertension treatments had good outcomes than those without (47.7% vs 31.0%, P=0.0001). After adjusted for age, heart diseases, baseline stroke severity, systolic blood pressure at admission, pneumonia, intravenous thrombolysis, and hospital stay, multivariate logistic regression indicated that premorbid hypertension treatment was related to an increased likelihood of good functional outcomes (OR: 2.21, 95% CI: 1.30 to 3.74, P=0.003). CONCLUSIONS: Less than half of the Chinese patients with hypertension were on drug treatment prior to stroke onset. Lack of premorbid hypertension treatment may have deteriorated functional outcomes of stroke. These findings emphasized the importance of improving hypertension treatment in Chinese, especially in whom at high risk of cerebrovascular diseases.

Hypertension unawareness among Chinese patients with first-ever stroke.

BACKGROUND: The low rates of hypertension treatment and control, partly due to its unawareness, are the main causes of the high stroke incidence in China. The purpose of this study was to evaluate hypertension unawareness amongst patients with first-ever stroke and to detect factors associated with its unawareness. METHODS: We selected those diagnosed with hypertension from patients with first-ever stroke registered in the Nanjing Stroke Registry Program between 2004 and 2014. These hypertensives were divided as being aware or unaware of their hypertension by using a brief questionnaire conducted shortly after the stroke. Multivariate logistic regression analysis was performed to identify potential factors associated with hypertension unawareness. RESULTS: Of the 5309 patients with first-ever stroke, 3732 (70.3%) were diagnosed with hypertension. Among which, 593 (15.9%) were unaware of their hypertension at the time of stroke onset. Lower-level of education (primary school or illiteracy) and smoking were associated positively with hypertension unawareness; while advanced age, overweight, diabetes mellitus, heart diseases and family history of stroke were associated negatively with hypertension unawareness. Annual data analyzed indicated that the rate of hypertension awareness increased during the past 11 years (r = 0.613, P = 0.045 for trends). CONCLUSIONS: A substantial proportion (15.9%) of Chinese patients with hypertension had not been aware of this covert risk until an overt stroke occurred. Hypertension unawareness was associated with lower educational levels and smoking, which address the importance of health education especially in these individuals.

Repetitive transcranial magnetic stimulation for rehabilitation of poststroke dysphagia: A randomized, double-blind clinical trial.

OBJECTIVE: This randomized, sham-controlled, double-blind study was conducted to investigate the effects of high-frequency versus low-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with poststroke dysphagia during early rehabilitation. METHODS: Forty patients with poststroke dysphagia were randomized to receive five daily sessions of sham, 3-Hz ipsilesional, or 1-Hz contralesional rTMS. Swallowing function, the severity of stroke and functional disability, and cortical excitability were examined before, immediately after five daily sessions, as well as the first, second, and third month after the last session. RESULTS: At baseline, no significant differences between groups were observed in terms of demographic and clinical rating scales. However, a significantly greater improvement in swallowing function as well as functional disability was observed after real rTMS when compared with sham rTMS, which remained 3 months after the end of the treatment sessions. In addition, 1-Hz rTMS increased cortical excitability of the affected hemisphere and decreased that of the non-affected hemisphere; however, 3-Hz rTMS only increased cortical excitability of the affected hemisphere. CONCLUSION: rTMS (both high and low frequency) improved swallowing recovery in patients with poststroke dysphagia, and the effects lasted for at least 3 months. SIGNIFICANCE: rTMS appears to be a beneficial therapeutic modality for patients with dysphagia during the early phase of stroke.

Shared and discrepant susceptibility for carotid artery and aortic arch calcification: A genetic association study.

Genome-wide association studies (GWASs) have identified several risk loci for coronary artery calcification. Four single-nucleotide polymorphisms (SNPs, rs1537370, rs1333049, rs2026458 and rs9349379) were associated with coronary artery calcification with P values less than 5 × 10(-8) in GWASs. It is unclear if these associations exist in other vascular beds. Thus, we evaluated the impacts of these four SNPs on carotid artery and aortic arch calcification in this study. Computed tomography was applied to quantify the calcification of carotid artery and aortic arch. 860 patients with stroke completed calcification quantification and genotype testing were included in data analysis. Each SNP was evaluated for the association with carotid artery calcification, and with aortic arch calcification using generalized linear model. Among the four tested SNPs, rs2026458 was associated with calcification in both carotid artery (ß = 0.31, 95% confidence interval [CI] 0.10-0.52, P = 0.003) and aortic arch (ß = 0.32, 95% CI 0.10-0.54, P = 0.004), while rs1333049 was only associated with carotid artery calcification (ß = 0.28, 95% CI 0.06-0.50, P = 0.011). In gender-stratified analyses, rs2026458 had significant impacts on carotid artery (P = 0.003) and aortic arch calcification (P = 0.008) in male, but not in female patients; while rs1537370 was significantly associated with carotid artery calcification in female (P = 0.013), but not in male patients. In conclusion, SNPs associated with coronary artery calcification may also increase the risk of calcification in other arteries such as carotid artery and aortic arch.

Mitochondrial DNA haplogroups and short-term neurological outcomes of ischemic stroke.

Stroke is one of the leading causes of death and long-term disability worldwide. Mitochondrial DNA (mtDNA) is a potential contributor for the sex differences of ischemic stroke heritability. Although mtDNA haplogroups were associated with stroke onset, their impacts on stroke outcomes remain unclear. This study aimed to evaluate the impacts of mtDNA haplogroups on short-term outcomes of neurological functions in patients with ischemic stroke. A total of 303 patients were included, and their clinical data and mtDNA sequences were analyzed. Based on the changes between baseline and 14-day follow-up stroke severity, our results showed that haplogroup N9 was an independent protective factor against neurological worsening in acute ischemic stroke patients. These findings supported that mtDNA variants play a role in post-stroke neurological recovery, thus providing evidences for future pharmacological intervention in mitochondrial function.

Association of heme oxygenase-1 gene rs2071746 polymorphism with vascular outcomes in patients with atherosclerotic stroke.

As an inducible isoform of heme oxygenase (HO), HO-1 was suggested to have an anti-oxidative stress, anti-inflammatory, anti-apoptotic and anti-proliferative effect. It was regarded as an important cytoprotective enzyme. We undertook this study to investigate whether HO-1 gene rs2071746 polymorphism was associated with clinical outcomes in atherosclerosis ischemic stroke patients. Between December 2009 and October 2012, consecutive atherosclerosis ischemic stroke patients were enrolled. The primary endpoint was the composite of vascular death, nonfatal ischemic stroke and myocardial infarct. A total of 961 patients were enrolled. After an average follow-up of 15.13 (SD=7.42) months, 89 patients (9.26%) had the primary endpoint. The cumulative incidence of the primary endpoint was significantly lower in A carriers (AT+AA) than TT genotype (7.9% vs. 12.2%, HR=0.648, 95% CI: 0.425-0.988, P=0.044). After adjustment for age, sex and other cardiovascular risk factors, we found that A carrier was an independent protective factor for atherosclerosis ischemic stroke (HR=0.646, 95% CI: 0.420-0.994, P=0.047). Age (HR=1.023, P=0.028) and low level of HDL (HR=1.772, P=0.012) were independent risk factors for the primary endpoint. In conclusion, HO-1 gene rs2071746 A allele carrier might be a protective factor for patients with atherosclerotic stroke.

Impacts of COX-1 gene polymorphisms on vascular outcomes in patients with ischemic stroke and treated with aspirin.

As the key point of function for aspirin to educe anti-platelet effects, cyclooxygenase-1 (COX-1) gene polymorphisms have long been suspected as a potential cause for aspirin nonresponsiveness. But this hypothesis has not been confirmed by large longitudinal studies. This study prospectively evaluated the impacts of COX-1 gene polymorphisms on stroke recurrence and other vascular events in a large cohort of Chinese patients with ischemic stroke and treated with aspirin. Between December 2009 and October 2012, consecutive patients with ischemic stroke and treated with aspirin were enrolled. Polymorphisms of four alleles (rs1330344, rs10306114, rs3842788 and rs5788) in COX-1 gene were determined at baseline. The primary endpoint was a composite of nonfatal ischemic stroke, myocardial infarction, and death from cardiovascular causes. Impacts of COX-1 gene polymorphisms on vascular outcomes were evaluated with multivariate analysis. A total of 859 patients were included in data analysis. The minor allele frequencies of rs1330344, rs10306114, rs3842788 and rs5788 were 38.53%, 0.12%, 6.64% and 5.53%, respectively. During 14.64 ± 7.44 months of follow-up, primary endpoint was observed in 67 (7.80%) patients. Incidence of primary endpoint was higher in patients with CC genotype of rs1330344 than in patients with CT or TT genotype (HR=1.916, 95% CI: 1.126-3.260, P=0.016). After being adjusted for potential confounding factors, rs1330344 CC genotype was still independently associated with incidence of primary endpoint (HR=1.958, 95% CI: 1.151-3.332, P=0.013). The impacts of other three tested polymorphisms on primary endpoint were unremarkable. In conclusion, in Chinese patients with ischemic stroke and treated with aspirin, CC genotype of rs1330344 may increase the risk of subsequent vascular events.