The TXA2R rs1131882, P2Y1 rs1371097 and GPIIIa rs2317676 three-loci interactions may increase the risk of carotid stenosis in patients with ischemic stroke.

BACKGROUND: The genetic risk factors for carotid stenosis are not fully understood. The aim of this study is to investigate the relationship between variants in platelet activation-relevant genes and carotid stenosis in patients with ischemic stroke (IS). METHODS: Eleven variants of platelet activation-relevant genes, aggregates of platelet-leukocyte, and platelet aggregation were examined in 236 IS patients with carotid stenosis and 378 patients without carotid stenosis. High-resolution B-mode ultrasound was used to assess carotid stenosis. Generalized multifactor dimensionality reduction (GMDR) methods were applied in analyzing gene-gene interactions to determine whether there was any interactive role of assessed variants in affecting risk of carotid stenosis. RESULTS: Platelet aggregation and aggregates of platelet-leukocyte showed higher value in patients with carotid stenosis, compared with patients without carotid stenosis. Excluding potential disturbance variables, these 11 variants were not associated with carotid stenosis. However, according to the GMDR analysis, gene-gene interactions among TXA2R rs1131882, P2Y1 rs1371097 and GPIIIa rs2317676 had a synergistic influence on carotid stenosis. The high-risk interactions between the three variants showed a relationship with higher platelet activation, and have independent associations with risk of carotid stenosis (OR = 2.72, 95% CI: 1.28-7.82, P = 0.001). CONCLUSION: The interactions among rs1131882, rs1371097 and rs2317676 perhaps increase the risk of symptomatic carotid stenosis, and maybe a potential marker for carotid stenosis. In this study, the combinatorial analysis made good use in elucidating complex risk factors in the heredity of carotid stenosis.

The secondary prevention of stroke according to cytochrome P450 2C19 genotype in patients with acute large-artery atherosclerosis stroke.

PURPOSE: To investigated the effectiveness of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype in patients with ischemic stroke (IS). METHODS: Between August 2009 and December 2011, 570 acute IS patients with acute large-artery atherosclerosis were randomly assigned to receive either combined clopidogrel and aspirin for the first 30 day, and clopidogrel thereafter (clopidogrel group, n=284) or aspirin monotherapy (aspirin group, n=286). CYP2C19 genotypes were measured and masked until the end-of-study. The primary outcome was a composite of IS, transient ischemic attack (TIA), myocardial infarction (MI), and death. RESULTS: During the 5 years follow-up, the primary outcome occurred in 105 patients (18.4%) (71 had IS, 10 had TIA, 12 had MI, and 12 died). There were no significant differences in the primary outcome between clopidogrel group and aspirin group (16.5% vs. 20.3%) or between carriers of the CYP2C19 reduced-function alleles and noncarriers (21.8% vs.15.7%). In patients with aspirin therapy, CYP2C19 polymorphism was not associated with the primary outcome. However, in patients treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele had a 3-fold higher adjusted risk for primary outcome compared with noncarriers (95% confidence interval, 1.23 to 8.74). CONCLUSIONS: Among IS patients treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had a significantly higher rate of adverse vascular events than did noncarriers. It should avoid prescribing clopidogrel to these patients with known CYP2C19 polymorphisms.

Dual therapy with clopidogrel and aspirin prevents early neurological deterioration in ischemic stroke patients carrying CYP2C19*2 reduced-function alleles.

PURPOSE: To investigate the associations between CYP2C19 genotypes and early neurological deterioration (END), and to carry out a stratified analysis of the effectiveness of clopidogrel alone and dual antiplatelet therapy with clopidogrel and aspirin for prevention of END according to CYP2C19 genotypes in ischemic stroke (IS) patients. METHODS: This was a prospective, observational, two-center study. A total of 375 acute IS patients were enrolled. Platelet aggregation was measured before and after the 7- to 10-day treatment. Clopidogrel resistance (CR) was assessed by adenosine diphosphate-induced platelet aggregation. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) genotypes were examined using mass spectrometry. The primary outcome was END during the 10 days after admission. RESULTS: Among the 375 patients, 144 patients received clopidogrel alone, 231 patients took clopidogrel plus aspirin, 153 patients (40.8%) had CR, 95 patients (25.3%) experienced END. Patients carrying CYP2C19*2 AG/AA (CYP2C19*2 reduced-function alleles) and CR were associated with a higher risk for END, and dual antiplatelet therapy was associated with a lower risk for END. Stratified analyses revealed that there was no significant difference in the incidence of END between patients not carryingCYP2C19*2 reduced-function alleles who received clopidogrel plus aspirin and those who received clopidogrel alone. However, dual antiplatelet therapy was more effective at reducing END and inhibiting platelet aggregation than clopidogrel alone for carriers of at least one CYP2C19*2 reduced-function allele. CONCLUSIONS: The frequency of END was very high after acute IS in the Chinese population. Dual therapy with clopidogrel and aspirin may be adequate for patients carrying CYP2C19*2 reduced-function alleles. Genetic testing may be useful to guide personalized and precise antiplatelet therapy. CLINICAL TRIAL REGISTRATION INFORMATION: The study described here is registered at http://www.chictr.org / (unique Identifier: ChiCTR-OCH-14004724).

Interactions among Variants in Eicosanoid Genes Increase Risk of Atherothrombotic Stroke in Chinese Populations.

BACKGROUND: Eicosanoids are lipid mediators that may play a role in ischemic stroke (IS). However, the association of variants in eicosanoid genes and these interactions with IS risk has not been investigated. The aim of the present study was to investigate the association of 11 variants in eicosanoid genes with IS and to determine whether these gene-gene interactions increase the risk of IS. METHODS: Eleven variants in prostaglandin H synthase-1 (PTGS1), PTGS2, thromboxane A2 synthase (TBXAS1), prostacyclin synthase (PTGIS), and prostaglandin E synthase (PTGES) genes were examined using mass spectrometry method in 297 patients with atherothrombotic stroke and 291 controls. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) method. Platelet aggregation and platelet-leukocyte aggregates were measured on admission. RESULTS: There were no significant differences in the genotype distributions of the 11 variants between patients and controls. However, GMDR analysis showed a significant gene-gene interaction among rs20417, rs5602, and rs41708, which scored 10 for cross-validation consistency and 9 for the sign test (P = .014). Logistic regression analysis showed that high-risk interaction among rs20417, rs5602, and rs41708 was an independent risk factor for atherothrombotic stroke (OR = 2.45, 95% CI: 1.33-3.27, P = .019). The high-risk interactive genotypes were associated with higher platelet aggregation and platelet-leukocyte aggregates. CONCLUSIONS: PTGS2 rs20417, PTGIS rs5602, and TBXAS1 rs41708 three-locus interactions may confer a higher risk for atherothrombotic stroke. The combinatorial analysis used in this study may be helpful to elucidate complex genetic risk for IS.

Platelet function-guided modification in antiplatelet therapy after acute ischemic stroke is associated with clinical outcomes in patients with aspirin nonresponse.

PURPOSE: To investigate the association of clinical outcomes with platelet function-guided modification in antiplatelet therapy in patients with ischemic stroke. RESULTS: Among 812 patients, 223 patients had aspirin nonresponse, 204 patients was modified in antiplatelet therapy after platelet function testing. Mean follow-up period was 4.8 ± 1.7 years (ranged from 1 to 6.4 years). The incidence rates of ischemic events, death, or bleeding events were not significantly different between the patients with and without antiplatelet therapy modification. However, in patients with aspirin nonresponse, antiplatelet therapy modification was associated with decreased ischemic events (hazard ratio, 0.67; 95% confidence interval [CI], 0.62-0.97; P = 0.01) and ischemic stroke (hazard ratio, 0.70; 95% CI, 0.63-0.98; P = 0.03) compared with no modification in antiplatelet therapy. CONCLUSIONS: In patients with aspirin nonresponse, platelet function-guided modification in antiplatelet therapy after an ischemic stroke was associated with significantly lower rate of ischemic events. The platelet function testing may be useful to guide antiplatelet therapy modification. METHODS: This is a retrospective, multicentre study. From August 2010 to December 2014, 812 patients with ischemic stroke underwent platelet function testing using platelet aggregation. Antiplatelet therapy modification was defined as any change in antiplatelet therapy after testing, including increasing aspirin dosage, adding an additional antiplatelet agent to aspirin, or switching to a more potent antiplatelet agent. The primary outcome was ischemic events. Secondary outcomes included death and bleeding events. Clinical outcomes were compared between patients with and without antiplatelet therapy modification using univariate and propensity score-adjusted analyses.

Stroke Subtypes and Topographic Locations Associated with Neurological Deterioration in Acute Isolated Pontine Infarction.

OBJECTIVE: This study investigated predictors of neurological deterioration (ND) in acute isolated pontine infarction. METHODS: Two hundred fifty-nine patients with acute isolated pontine infarctions identified using diffusion-weighted imaging were retrospectively analyzed. The patients were divided according to the presence/absence of ND, defined as increased (≥2 units) National Institutes of Health Stroke Scale scores 5 days after onset. Pontine infarctions comprised 3 stroke subtypes: vertebrobasilar large-artery disease, basilar artery branch disease (BABD), and small-artery disease (SAD), according to basilar artery atherosclerosis severity and lesion extent of the transverse axial plane. Topographic locations of longitudinal pontine infarctions in the axial plane were divided into upper, middle, lower, and whole. RESULTS: Of the 259 patients (male : female = 136:123, 68.84 ± 10.24), only 27.4% exhibited ND. The prevalence was significantly increased in females, whereas smoking was significantly decreased in patients with ND. BABD and lower pontine infarctions were significantly more frequent in patients with ND (70.4% and 43.7%, respectively) than in patients without ND (51.6% and 30.3%, respectively). SAD and upper pontine infarctions were significantly less frequent in patients with ND (16.9% and 7.0%, respectively) than in patients without ND (30.3% and 23.4%, respectively). BABD and lower pontine infarctions were positively related to ND. CONCLUSIONS: This is the first study to demonstrate that BABD and lower pons lesions are predictors of ND in acute isolated pontine infarction. These findings indicate the potential importance of early identification of stroke subtypes and topographic locations in the prevention of ND in patients with suspected pontine infarction.

Ischemic stroke risk in a southeastern Chinese population: Insights from 5-lipoxygenase activating protein and phosphodiesterase 4D single-nucleotide polymorphisms.

BACKGROUND/PURPOSE: Through a genome-wide linkage scan, an Icelandic genetic research group identified two new genes associated with ischemic stroke: the 5-lipoxygenase activating protein (ALOX5AP) gene and the phosphodiesterase 4D (PDE4D) gene. Because they regulate arterial inflammation and are closely related to atherosclerosis and plaque instability, these two mutated genes have become a research hotspot. The purpose of this study was to investigate the association between the risk of ischemic stroke and single-nucleotide polymorphisms (SNPs) in the ALOX5AP and PDE4D genes in a southeastern Chinese population. METHODS: A total of 459 patients with stroke and 462 control individuals were recruited in the study. Four ALOX5AP SNPs (SG13S32, SG13S42, SG13S89, and SG13S114), and three PDE4D SNPs (SNP83, SNP87, and SNP45) were studied. SNP genotypes were determined by polymerase chain reaction amplification followed by allele-specific primer extension, with detection by matrix-assisted laser desorption/ionization time-of-flight. Data were coded and entered in SPSS Windows (version 16.0). Odds ratios and 95% confidence intervals were calculated using multivariate logistic regression analysis. Generalized multifactor dimensionality reduction (GMDR) analysis was applied to detect gene-gene interactions. RESULTS: No statistically significant differences were found in the SNP genotype frequencies between cases and controls for the seven SNPs studied. GMDR analysis revealed no evidence of interactions between these seven polymorphic sites and an increased stroke risk. In addition, no association between different stroke types and the control group was detected. Results showed that only the ALOX5AP gene, and specifically the rs9551963 and rs4769060 genotypes, exhibited significantly different distributions between the stroke and control groups in female participants. CONCLUSION: No association was found between SNPs of ALOX5AP or PDE4D and the risk of overall ischemic stroke in a southeastern Chinese population. Interactions between these two genes were not risk factors for cerebral infarction. In atherothrombotic and small-artery disease subtypes, none of the seven SNPs was associated with any stroke risk; however, the ALOX5AP gene might be related to ischemic stroke incidence in females.

Stability of isoflavone isomers in steamed black soybeans and black soybean koji stored under different conditions.

Steamed black soybeans and black soybean koji, a potentially functional food additive, were stored at 4 or 25 degrees C with or without deoxidant and desiccant for 120 days. After storage, steamed black soybeans and koji showed various extents of reduction in isoflavone contents dependent on storage temperature, packaging condition, and the kind of isoflavone isomer. Generally, black soybeans and koji showed the highest residual of isoflavone when they were stored at 4 degrees C with deoxidant and desiccant. Under this storage condition, beta-glucosides (daidzin, glycitin, and genistein), acetyl glucosides (acetyldaidzin, acetylglycitin, and acetylgenistin), manlonyl glucosides (malonyldaidzin, malonglycitin, and malonylgenistin), and aglycones (daidzein, glycitein, and genistin) in steamed black soybeans exhibited residuals of 100.1-100.9, 92.0-99.4, 90.0-94.0, and 77.2-78.8%, respectively, of their original contents after 120 days of storage. Meanwhile, the residuals found in black soybean koji were 77.8-90.0, 13.1-88.9, 66.7-85.5, and 76.4-80.6%, respectively.

Heating affects the content and distribution profile of isoflavones in steamed black soybeans and black soybean koji.

Steamed black soybeans and black soybean koji, a potentially functional food additive, were subjected to heating at 40-100 degrees C for 30 min. It was found that steamed black soybeans and black soybean koji after heating at 80 degrees C or higher generally showed reduced contents of malonylglucoside, acetylglucoside, and aglycone isoflavone and an increased content of beta-glucoside. A lower reduction in malonylglucoside and acetylglucoside isoflavone but greater reduction in aglycone content was noted in steamed black soybeans compared to black soybean koji after a similar heat treatment. After 30 min of heating at 100 degrees C, steamed black soybean retained ca. 90.3 and 83.8%, respectively, of its original malonylglucoside and acetylglucoside isoflavone, compared to lower residuals of 80.9 and 78.8%, respectively, for black soybean koji. In contrast, the heated black soybeans showed an aglycone residual of 68.0%, which is less than the 80.0% noted with the heated black soybean koji.