Variants in matrix metalloproteinase-9 gene are associated with hemorrhagic transformation in acute ischemic stroke patients with atherothrombosis, small artery disease, and cardioembolic stroke.

OBJECTIVE: The potential effect of matrix metalloproteinase-9 (MMP-9) variants and these variants interactions on hemorrhagic transformation (HT) risk after ischemic stroke (IS) remain unclear. The aims of present study were to investigate the associations of six variants in MMP-9 with HT, and these variants interactions whether related to increased HT risk. METHOD: A total of 705 patients with IS who were admitted to the participating hospitals within 48 hr of symptom onset were consecutively enrolled between March 2014 and December 2016. HT was confirmed by brain computed tomography (CT) scan during 14 days from stroke onset. Six variants of MMP-9 gene were measured by mass spectrometry. Interactions of gene variant-gene variant were assessed through generalized multifactor dimensionality reduction method (GMDR). RESULTS: HT occurred in 104 (14.8%) patients. There were no differences in genotypes for the six variants between patients with and without HT using univariate analysis (all p > 0.05). GMDR analysis revealed that there was a synergistic effect of gene variant-gene variant interactions between rs3918242 and rs3787268 in MMP-9 gene. Cox regression analysis showed that high-risk interactions of rs3918242 and rs3787268 were associated with increased risk of HT after adjusting for covariates (hazard ratio: 2.08; 95% confidence interval: 1.34-7.85; p = 0.016). CONCLUSION: Incidence of HT is common in acute IS in Chinese population. The mechanisms leading to HT are most likely multifactorial. Two-loci interactions of rs3918242 and rs3787268 in MMP-9 gene may confer a higher risk for HT.

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.

Aspirin plus clopidogrel may reduce the risk of early neurologic deterioration in ischemic stroke patients carrying CYP2C19*2 reduced-function alleles.

OBJECTIVES: The mechanisms of early neurologic deterioration (END) and prevention strategies for END are not completely understood. The aim of this study was to investigate the association between CYP2C19*2 variants and END, and the effectiveness of antiplatelet therapy for prevention of END according to CYP2C19*2 genotypes in patients with ischemic stroke (IS). MATERIALS AND METHODS: This was a two-center, randomized controlled study. Between August 2009 and December 2011, 570 IS patients were randomly assigned to clopidogrel plus aspirin group (n = 284) or aspirin alone group (n = 286). Platelet aggregation and platelet-leukocyte aggregates were measured before and after 7-10 days of treatment. CYP2C19*2 (rs4244285) genotypes were examined using mass spectrometry. The primary outcome was END during the 10 days of admission. RESULTS: Among the 570 patients, 121 (21.2%) patients suffered from END. Carriers of CYP2C19*2 reduced-function alleles were associated with higher incidence of END (26.8% in carriers vs. 16.6% in noncarriers, P = 0.004). The incidence of END was lower in the clopidogrel plus aspirin group than in the aspirin alone group (17.6 vs. 24.8%, P = 0.032). Stratified analyses revealed that clopidogrel plus aspirin could be more effective in reducing END than aspirin alone for carriers of CYP2C19*2 reduced-function alleles (18.8 vs. 34.9%, P = 0.006). However, there was no significant difference in incidence of END between dual therapy group and monotherapy group for noncarriers (16.7 vs. 16.6%, P = 0.998). CONCLUSIONS: Dual therapy with clopidogrel and aspirin may be adequate for prevention of END in carriers of CYP2C19 reduced-function alleles, but not for noncarriers. Our findings may be useful to guide precise antiplatelet therapy, and decrease the risk of END.

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).

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.