Interactions among COX-2, GPIIIa and P2Y1 variants are associated with aspirin responsiveness and adverse events in patients with ischemic stroke

Wang

et al. 2018

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PurposeThe relationship between response to clopidogrel and early neurological deterioration (END) after acute ischemic stroke (IS) is not well defined. The aim of present study was to evaluate the associations of clopidogrel resistance (CR) with END, and stratified analyze the effectiveness of clopidogrel alone and clopidogrel plus aspirin for the prevention of END.ResultsA total of 375 patients, 144 patients were received clopidogrel alone, 231 patients took clopidogrel plus aspirin. CR occurred in 153 patients (40.8%). 95 (25.3%) patients developed END within the first 10 days. Platelet aggregation was higher on admission, and inhibition of platelet aggregation was significantly lower in patients with END than patients without END. Diabetes mellitus, CR, and clopidogrel plus aspirin were independently associated with END. Dual antiplatelet therapy with aspirin and clopidogrel can inhibit both arachidonic acid (AA)-induced and ADP-induced platelet aggregationMethodsThis was a prospective, two-center study. A total of 375 IS patients taking clopidogrel alone or clopidogrel plus aspirin were enrolled. Platelet aggregation was measured before and after the 7–10 day treatment. CR was assessed by adenosine diphosphate (ADP)-induced platelet aggregation. The primary endpoint was END within the 10 days after admission. The secondary endpoint was a composite of recurrent ischemic stroke, myocardial infarction, and death during the 10 days after admission.ConclusionsCR and END are fairly common after acute IS. CR is associated with higher risk of END. Clopidogrel plus aspirin combination therapy provides greater inhibition of platelet aggregation, and may afford protection against END.

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Response to clopidogrel is associated with early neurological deterioration after acute ischemic stroke

Wang

et al. 2018

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“…COX and platelet receptors or glycoprotein receptor are involved in platelet activation, and are inhibited by aspirin. Although accumulating evidences have suggested that aspirin-relevant genetic variants may affect aspirin responsiveness and clinical adverse outcomes in IS patients [ 10 , 26 ], the CYP2C19 is not involved in action of aspirin and thus do not affect aspirin responsiveness and clinical adverse outcomes.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou

et al. 2018

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PurposeTo investigated the effectiveness of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype in patients with ischemic stroke (IS).MethodsBetween 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.ResultsDuring 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).ConclusionsAmong 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.

“…Platelet activation was associated the pathophysiology of atherogenesis and IS [ 15 , 16 , 18 , 19 ]. Our previous studies have administrated that the variants of platelet activation-relevant genes ( TXA2R, GPIIIa, P2Y12, P2Y1, TXAS1 ) not only increase the risk for IS, but also are associated with response to antiplatelet drugs and clinical adverse outcomes after IS [ 13 , 22 , 25 , 27 , 28 ]. However, the associations of the variants in platelet activation-relevant genes with carotid plaque vulnerability were not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that genes contribute to the complex diseases only by interactions with other genes, and the effects of individual variant may be too small to be detected [ 30 ]. Our previous studies have administrated that the GMDR analysis may be helpful to understand complex genetic etiology of IS [ 22 , 25 , 27 , 28 ]. However, few studies used the GMDR approach to investigate complex genetic risk for carotid plaque vulnerability.…”

Section: Discussionmentioning

confidence: 99%

Interactions among variants in TXA2R, P2Y12 and GPIIIa are associated with carotid plaque vulnerability in Chinese population

Luo

et al. 2018

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PurposeThe associations between variants in platelet activation-relevant genes and carotid plaque vulnerability are not fully understood. The aim of the present study was to investigate the associations of the variants in platelet activation-relevant genes and interactions among these variants with carotid plaque vulnerability.ResultsThere were no significant differences in the frequencies of genotypes of the 11 variants between patients and controls. Among 396 patients, 102 patients had not carotid plaque, 106 had VP, and 188 had SP. The 11 variants were not independently associated with risk of carotid plaque vulnerability after adjusting for potential confounding variables. However, the GMDR analysis showed that there were synergistic effects of gene-gene interactions among TXA2Rr s1131882, GPIIIa rs2317676 and P2Y12 rs16863323 on carotid plaque vulnerability. The high-risk interactions among the three variants were associated with high platelet activation, and independently associated with the risk of carotid plaque vulnerability.MethodsEleven variants in platelet activation-relevant genes were examined using mass spectrometry methods in 396 ischemic stroke patients and 291controls. Platelet-leukocyte aggregates and platelet aggregation were also measured. Carotid plaques were assessed by B-mode ultrasound. According to the results of ultrasound, the patients were stratified into three groups: non-plaque group, vulnerable plaque (VP) group and stable plaque (SP) group. Furthermore, gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods.ConclusionsThe rs1131882, rs2317676, and rs16863323 three-loci interactions may confer a higher risk of carotid plaque vulnerability, and might be potential markers for plaque instability.