Genetic variants of PTGS2, TXA2R and TXAS1 are associated with carotid plaque vulnerability, platelet activation and TXA2 levels in ischemic stroke patients

Background: Platelet-leukocyte aggregation (PLA) and platelet activation are found to be on the higher side in ischemic stroke patients. The correlation of PLA with clinical features has not been intensively investigated and the influence of genetic factors on PLA is still unexplored. The interaction of platelets with leukocytes is mainly determined by the proteins encoded by six genes: P-Selectin (SELP encodes CD62P) on the thrombocyte binding to P-Selectin-Glycoprotein-Ligand-1 (PSGL1) on the leukocyte, intracellular-adhesion-molecule 2 (ICAM2) interacting with Integrin alpha M (ITGAM) and Glycoprotein 1b-alpha (GP1BA) binding to Integrin alpha L (ITGAL). Methods: Seventy-nine patients with acute ischemic stroke and 151 controls without vascular disease from a single German center were enrolled. A neurologist and a neuroradiologist ascertained clinical and radiological features. PLA and platelet activation were analyzed using flow cytometry with various antibodies. Coding as well as tagging SNPs in six genes determining PLA were genotyped. Three groups of parameters were correlated with each other: (i) clinical and radiological parameters, (ii) laboratory parameters, (iii) genetic parameters. For the comparisons, robust nonparametric statistical tests were applicable. Results: PLA and platelet activation were higher in ischemic stroke patients compared to controls. Both, anticoagulant and antiplatelet treatment in the patient group affected platelet activation but not PLA. PLA correlated weakly with measures of stroke severity but not with thrombus length or stroke etiology. The association of SNP rs2228315 in the P-Selectin Glycoprotein Ligand-1-gene (PSGL1) with ischemic stroke and platelet activation was significant before correction for multiple testing while a trend was observed for the association with PLA. Regression analysis revealed that (i) platelet activation was an independent determinant of stroke, (ii) that PLA correlated with stroke, sex, age and platelet activation and (iii) that platelet activation correlated only with stroke. None of the SNPs survived in the regression analysis for stroke, PLA or platelet activation as dependent variables. Conclusions: The most important result of our study is that PLA and platelet activation are independent of other vascular risk factors correlated with stroke in our sample. In addition, we identified the missense SNP rs2228315 in the PSGL1-gene as a candidate polymorphism for ischemic stroke-related PLA. Association between this SNP and stroke as well as coronary artery disease has also been shown by two other studies.

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Predisposing roles of paraoxonase-1 genetic variants in Korean ischemic stroke patients

Genes & Genomics ◽

10.1007/s13258-015-0287-0 ◽

2015 ◽

Vol 37 (7) ◽

pp. 579-586 ◽

Cited By ~ 2

Author(s):

Yunkyung Cho ◽

Jung Oh Kim ◽

Young Joo Jeon ◽

Gun Ho Choi ◽

Jee Soo Shin ◽

...

Keyword(s):

Ischemic Stroke ◽

Genetic Variants ◽

Paraoxonase 1 ◽

Stroke Patients

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Genetic Variability of SRC Family Kinases and Its Association with Platelet Hyperreactivity and Clinical Outcomes: A Systematic Review

Current Pharmaceutical Design ◽

10.2174/1381612824666171213105002 ◽

2018 ◽

Vol 24 (5) ◽

pp. 628-640 ◽

Cited By ~ 3

Author(s):

Lukasz Milanowski ◽

Fazila Rasul ◽

Sylwia Natalia Gajda ◽

Ceren Eyileten ◽

Jolanta Siller-Matula ◽

...

Keyword(s):

Myocardial Infarction ◽

Systematic Review ◽

Ischemic Stroke ◽

Genetic Variability ◽

Clinical Outcomes ◽

Platelet Activation ◽

Genetic Variants ◽

Clinical Manifestations ◽

Src Family Kinases ◽

Platelet Receptors

Background: Platelet hyperactivity has been implicated in many cardiovascular (CV) events such as ischemic stroke, myocardial infarction and CV death. Genetic variability of platelet receptors has been shown to impact Src family kinases (SFKs) activation and in turn influence platelet activation. SFKs are important signal transmitters in platelets, interacting with several receptors as GPIIB/IIIa, GPIb, PEAR 1, GPIa, GPVI, PECAM and CD148. Methods: In this review, we focused on genetic variants of platelet receptors whose signals are transmitted mainly by SFKs and may be associated with clinical manifestations of platelet hyperactivation like MI or IS. Results: The genetic variants of platelet receptors, the signals of which are transmitted by SFKs, and the associated clinical manifestations in platelet hyperactivation, have been examined. The most extensively studied receptors were glycoprotein polymorphisms. The greatest numbers of genetic variants were analyzed in GPIb. GPIIb/IIIa receptor polymorphisms were also well analyzed and many studies highlighted their associations with ischemic stroke (IS) and myocardial infarction (MI). However, there are a number of conflicting studies finding that GPIIb/IIIa receptor polymorphisms may not influence platelet hyperactivity. Moreover, variability within some other receptors like GPVI, PECAM, PEAR1, and CD148 was analyzed only in single studies. Conclusions: Src family kinases are one of the most important signal transmitters in platelets. Some receptors have well documented interactions with SFKs, while other have not been examined in humans or data about its association originated from single studies. Further studies are necessary to confirm the findings and reduce falsepositive associations.

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APOEϵ2 allele is an independent risk factor for vulnerable carotid plaque in ischemic stroke patients

Neurological Research ◽

10.1179/1743132814y.0000000385 ◽

2014 ◽

Vol 36 (11) ◽

pp. 950-954 ◽

Cited By ~ 3

Author(s):

Beata Blazejewska-Hyzorek ◽

Grazyna Gromadzka ◽

Marta Skowronska ◽

Anna Czlonkowska

Keyword(s):

Risk Factor ◽

Ischemic Stroke ◽

Carotid Plaque ◽

Independent Risk Factor ◽

Stroke Patients

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In Vivo Platelet Activation in Ischemic Stroke Patients

Stroke ◽

10.1161/01.str.0000092400.93742.81 ◽

2003 ◽

Vol 34 (10) ◽

Cited By ~ 4

Author(s):

Marina Karakantza ◽

Alice Maniatis ◽

C. Ioannis Metallinos ◽

Thodoros Papapetropoulos ◽

Christos Paschalis

Keyword(s):

Ischemic Stroke ◽

Platelet Activation ◽

Stroke Patients

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Pathophysiological Mechanisms of Carotid Plaque Vulnerability: Impact on Ischemic Stroke

Archivum Immunologiae et Therapiae Experimentalis ◽

10.1007/s00005-012-0192-z ◽

2012 ◽

Vol 60 (6) ◽

pp. 431-442 ◽

Cited By ~ 34

Author(s):

Jaroslav Pelisek ◽

Hans-Henning Eckstein ◽

Alma Zernecke

Keyword(s):

Ischemic Stroke ◽

Carotid Plaque ◽

Plaque Vulnerability ◽

Pathophysiological Mechanisms

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Association between Circulatory and Plaque Resistin Levels with Carotid Plaque Instability and Ischemic Stroke Events

The Heart Surgery Forum ◽

10.1532/hsf.2071 ◽

2018 ◽

Vol 21 (6) ◽

pp. E448-E463

Author(s):

Ivana Jurin ◽

Frane Paić ◽

Stela Bulimbašić ◽

Igor Rudež ◽

Lovorka Đerek ◽

...

Keyword(s):

Logistic Regression ◽

Regression Analysis ◽

Ischemic Stroke ◽

Carotid Artery ◽

Carotid Artery Stenosis ◽

Carotid Plaque ◽

High Grade ◽

Plaque Vulnerability ◽

Histological Features ◽

Plaque Instability

ses of ischemic stroke. The risk of ischemic stroke increases with the degree of carotid stenosis and plaque vulnerability. The aim of this study was to investigate the association of circulating and plaque resistin levels with plaque vulnerability and ischemic stroke events in patients with moderate- to high-grade carotid artery stenosis. Methods: 40 patients with ischemic stroke events and 38 neurologically asymptomatic patients scheduled for carotid endarterectomy were recruited for this study. Fasting blood samples for laboratory analysis were collected preoperatively and serum resistin levels were measured by enzyme-linked immunosorbent assays. Carotid endarterectomy specimens were analyzed according to the gold-standard procedure of histological classification. Plaque resistin expression was determined by standard immunohistochemical procedure. Results: Serum resistin levels and resistin plaque expression were found to be significantly higher in subjects with unstable carotid plaque (P < .001) while significantly higher serum resistin levels were also present in patients with ischemic stroke events (P < .001). In univariate stepwise logistic regression analysis, higher serum resistin levels were significantly associated with plaque instability (OR 2.223, 95% CI 1.488-3.320, P < .0001) and ischemic stroke events (OR 1.237, 95% CI 1.079-1.420, P = .002). There was also a significant association between higher serum and plaque resistin expression (OR 1.663, 95% CI1.332-2.077, P < .0001). These associations remained significant in all models of multivariate logistic regression analysis. High serum and plaque resistin levels were also significantly associated with specific histological features of plaque instability. Conclusion: The results suggests that serum resistin levels may be used as a potential biomarker of plaque vulnerability and ischemic stroke events in patients with moderate- to high-grade carotid artery stenosis and highlight the possible relationship that plaque resistin expression has with histological features of plaque vulnerability.

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