Relationship between Aspirin Resistance and Gene Polymorphism in Chinese Patients with Cerebral Infarction: A Systematic Review and Meta-Analysis

Introduction This study aimed to evaluate the predictive potential of prostaglandin-endoperoxide synthase 1 ( PTGS1 ) and platelet endothelial aggregation receptor-1 ( PEAR1 ) gene polymorphisms, in combination with biochemical and demographic factors, for aspirin resistance (AR) and recurrence with cerebral infarction (CI) in Chinese patients. Methods A retrospective study was conducted on 280 patients diagnosed with CI and admitted to the Department of Neurology, Affiliated Hospital of Beihua University, between January and December 2021. Based on follow-up via telephone, patients were categorized into recurrent (n = 97) and non-recurrent (n = 183) groups. Clinical data, including age, sex, smoking and alcohol history, presence of coronary heart disease, diabetes, and hypertension, were collected. Laboratory indices measured upon admission included hemoglobin, triglycerides, total cholesterol, uric acid, and homocysteine (HCY) levels. Genotyping for PEAR1 and PTGS1 was performed. Univariate and multivariate logistic regression analyses were conducted to identify independent predictors of recurrence. A combined prediction model was developed, and receiver operating characteristic (ROC) curves were used to evaluate predictive performance. Results Significant differences were observed between the recurrent and non-recurrent groups in the distribution of PEAR1 and PTGS1 genotypes, the presence of hypertension, and levels of HCY ( p < 0.05). Multivariate logistic regression identified PEAR1 and PTGS1 polymorphisms, as well as elevated HCY, as independent predictors of cerebral infarction recurrence ( p < 0.05). ROC analysis demonstrated the following area under the curve (AUC) values for predicting recurrence: PEAR1 = 0.529, PTGS1 = 0.642, HCY = 0.696, and the combined prediction model = 0.721. The combined model showed significantly improved predictive value compared to individual markers ( p < 0.05). Conclusion PEAR1 and PTGS1 gene polymorphisms, when integrated with biochemical markers, such as HCY, could effectively predict the risk of recurrence in patients with cerebral infarction. The combined model has offered superior predictive value, supporting its potential clinical utility in guiding antiplatelet therapy for individualized risk stratification.

Platelet endothelial aggregation receptor 1 (PEAR1) and prostaglandin endoperoxide synthase 1 (PTGS1) polymorphisms can affect laboratory aspirin resistance. However, the impact of genetic polymorphisms on the recurrence of ischemic stroke (IS) patients treated with aspirin is not fully understood. This study aimed to examine the relationship between gene polymorphisms of PEAR1 and PTGS1 and IS recurrence in patients treated with aspirin. Peripheral blood samples were collected from 174 patients with nonrecurrent IS and 34 with recurrent IS after aspirin treatment. Follow-up was performed on all patients. PEAR1 rs12041331 and PTGS1 rs10306114 polymorphisms were determined using the PCR fluorescence probe method. And the correlations of them with the clinical characteristics were examined by multivariable logistic regression analysis. The distribution frequencies of PEAR1 rs12041331 and PTGS1 rs10306114 genotypes were in Hardy-Weinberg equilibrium, and there was no significant difference in the distribution of PEAR1 rs12041331 polymorphism. Compared to the nonrecurrent group, the AA genotype of the PTGS1 polymorphism was more frequent in the recurrent group (59.77% vs 35.29%, P = .003), and the A allele also showed a higher frequency than the G allele in the recurrent group (P = .001). Multivariable logistic regression analysis showed that smoking (OR = 5.228, 95% CI: 1.938-14.102, P = .001), coronary heart disease (OR = 4.754, 95% CI: 1.498-15.089, P = .008), and the polymorphism at PTGS1(A>G) AA/AG + GG (OR = 2.955, 95% CI: 1.320-6.616, P = .008) were independently associated with IS recurrence in Chinese patients. Our findings suggested that PTGS rs10306114 polymorphisms should receive more attention in the use of aspirin in patients with IS.

PEAR1/EAF1 deficiency impairs aspirin responsiveness in atherosclerotic endothelium: A novel mechanism of atypical aspirin resistance.

1. Genetic polymorphisms in platelet endothelial aggregation receptor 1 (PEAR1) were associated with responsiveness to aspirin and P2Y12 receptor antagonists. This study aimed to investigate whether PEAR1 polymorphism is associated with ticagrelor pharmacodynamics in healthy Chinese subjects.2. The in vitro inhibition of platelet aggregation (IPA) was evaluated before and after ticagrelor incubated with platelet-rich plasma from 196 healthy Chinese male subjects. Eight polymorphisms at PEAR1 locus were genotyped. Eighteen volunteers (six in each rs12041331 genotype group) were randomly selected. After a single oral 180 mg dose of ticagrelor, plasma levels of ticagrelor and the active metabolite AR-C124910XX were measured and pharmacodynamics parameters including IPA and VASP-platelet reactivity index (PRI) were assessed.3. No significant difference in ticagrelor pharmacokinetics among rs12041331 genotype was observed. As compared with rs12041331 G allele carriers, AA homozygotes exhibited increased IPA after 15 μM ticagrelor incubation (p < 0.01), increased area under the time-effect curve of IPA and lower PRI at 2 h after ticagrelor administration (p < 0.05, respectively). Rs4661012 GG homozygotes showed increased IPA after 50 μM ticagrelor incubation as compared to T allele carriers (p < 0.01).4. PEAR1 polymorphism may influence ticagrelor pharmacodynamics in healthy Chinese subjects.

Aspirin resistance has an incidence of 5%-65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A2 receptor (TXA2 receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by PLA2G7) and platelet endothelial aggregation receptor-1 (PEAR1, encoded by PEAR1) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1, TBXA2R, PLA2G7, PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB2 ELISA kit. Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233-0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080-6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590-42.638). A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931-rs7756935) polymorphisms.

ObjectivesTo investigate the association of aspirin resistance (AR) with the plasma 4‐hydroxynonenal (4‐HNE) level and its impact on recurrent cerebral infarction (CI) in patients with acute cerebral infarction (ACI) who were receiving aspirin therapy.MethodsOne hundred and fifty‐four ACI patients who previously received aspirin therapy (100 mg/day) were enrolled. Whole urine (for measuring 11dhTXB2 and creatinine) along with blood (for measuring the plasma 4‐HNE level) were collected at least 7 days after the patients received aspirin. A cutoff of 1500 pg/mg of 11dhTXB2/ creatinine was used to determine AR. A follow‐up period to monitor recurrence CI events was 1 year. In addition, blood testing was performed when the patients were first admitted to hospital.ResultsForty‐six of the 154 enrolled patients (29.9%) were found to be AR. No statistical difference in age, sex, hypertension, diabetes mellitus, coronary disease, smoking status, NIHSS score, TOAST classification, platelet count, thrombocytocrit, LDL‐C, HDL‐C, TG, and TC was found between the AR and aspirin‐sensitive (AS) patients, but the plasma 4‐HNE level was found to be higher in the AR patients than AS patients (p < .05). Multiple logistic regression analysis showed that the 4‐HNE level was associated with a higher risk of AR (OR = 1.034; 95% CI = 1.011–1.058; p < .05). Moreover, 1‐year follow‐up showed that AR was more prevalent in patients with recurrent CI (26 (56.6%)) than those without (20/(43.5%)) (p < .001).ConclusionsThe plasma 4‐HNE level is strongly associated with AR and thus may be a factor contributing to AR. Patients with AR have a greater risk of recurrence CI.

Although platelets lack nuclei and are the smallest circulating human cells, they play an integral and complex role in the process of thrombosis, both physiological and pathophysiological. Activation and aggregation of platelets play a central role in the propagation of intracoronary thrombi after (1) spontaneous atherosclerotic plaque disruption that results in myocardial ischemia or infarction in the acute coronary syndromes (ACS), or (2) the mechanical disruption that results from percutaneous coronary intervention (PCI). Platelets initially adhere to collagen and von Willebrand factor at the site of the disrupted plaque, resulting in an initial platelet monolayer. After activation, platelets release secondary agonists such as thromboxane A2 and adenosine diphosphate (ADP), which in combination with thrombin generated by the coagulation cascade result in stimulation and recruitment of additional platelets.1,2 With this pathophysiological background, it is not surprising that antiplatelet therapy is a cornerstone of the management of patients with ACS, especially those undergoing PCI.3–5 See p 3171 Aspirin inhibits cyclooxygenase (COX) by irreversible acetylation, which prevents the production of thromboxane A2. The antithrombotic effect of aspirin results from the decreased production of this prothrombotic, vasoconstrictive substance. Aspirin is effective in the short- and long-term prevention of adverse vascular events in high-risk patient groups, including those with ACS, stroke and peripheral arterial disease.6 Aspirin also has been shown to reduce the frequency of ischemic complications after PCI.7,8 Despite the impressive and consistent effects of aspirin in reducing adverse events in a variety of ischemic heart disease states, a significant rate of such events persists, and more potent antiplatelet agents, glycoprotein IIb/IIIa inhibitors, and thienopyridines have been developed. The thienopyridines irreversibly inhibit ADP binding to the P2Y12 receptor on the platelet surface. By blocking this receptor, these agents interfere with platelet activation, degranulation, and—by inhibiting the …

Aspirin resistance (AR) is a pressing problem in current ischemic stroke care. Although the role of genetic variations is widely considered, the data still remain controversial. Our aim was to investigate the contribution of genetic features to laboratory AR measured through platelet aggregation with arachidonic acid (AA) and adenosine diphosphate (ADP) in ischemic stroke patients. A total of 461 patients were enrolled. Platelet aggregation was measured via light transmission aggregometry. Eighteen single-nucleotide polymorphisms (SNPs) in ITGB3, GPIBA, TBXA2R, ITGA2, PLA2G7, HMOX1, PTGS1, PTGS2, ADRA2A, ABCB1 and PEAR1 genes and the intergenic 9p21.3 region were determined using low-density biochips. We found an association of rs1330344 in the PTGS1 gene with AR and AA-induced platelet aggregation. Rs4311994 in ADRA2A gene also affected AA-induced aggregation, and rs4523 in the TBXA2R gene and rs12041331 in the PEAR1 gene influenced ADP-induced aggregation. Furthermore, the effect of rs1062535 in the ITGA2 gene on NIHSS dynamics during 10 days of treatment was found. The best machine learning (ML) model for AR based on clinical and genetic factors was characterized by AUC = 0.665 and F1-score = 0.628. In conclusion, the association study showed that PTGS1, ADRA2A, TBXA2R and PEAR1 polymorphisms may affect laboratory AR. However, the ML model demonstrated the predominant influence of clinical features.

Platelets play a critical role in the pathophysiology of atherothrombotic disease. A pivotal event contributing to the understanding of platelet-dependent clot formation was the development of the platelet aggregometer in 1962.1 An aggregometer specifically measures the ability of platelets to adhere via glycoprotein IIb/IIIa (integrin αIIbβ3), and thousands of articles using this technique have been published, characterizing platelet function; however, the usefulness of these measurements remains unclear. Whereas the aggregometer and related techniques that measure platelet aggregation or glycoprotein expression have led to large amounts of data characterizing platelet function in various settings, the clinical importance of measurable differences in platelet function is still debated.2 The use of platelet function testing is established in rarer platelet abnormalities, such as the autosomal recessive bleeding disorder Glanzmann thrombasthenia,3 but no clear consensus has been reached on its usefulness for highly prevalent diseases caused by platelet-dependent thrombosis, such as myocardial infarction. A major factor for this discrepancy is that many of the platelet function defects that lead to bleeding are known to be caused by a single defect, whereas thrombosis in the setting of cardiovascular disease is presumed to be multifactorial. Article p 2490 The evolution of platelet function studies in various clinical settings has led to the realization that wide interindividual variability exists in the platelet activation response.4,5 What accounts for this variability? Only a few studies have systematically examined this question. Platelet function has been established as markedly dependent on the type of agonist used, the agonist concentration, and the concomitant use of antiplatelet therapy.6 In addition, in the large population-based Framingham Heart Study, O’Donnell and colleagues7 have demonstrated that heritable factors play a major role in determining platelet aggregation, as opposed to measured covariates. Less clear from the current literature is the direct …

Introduction: Platelet endothelial aggregation receptor 1 (PEAR1) triggers platelet aggregation and is expressed in platelets and endothelial cells. Genome-wide association studies (GWAS) showed an association between platelet function and single-nucleotide polymorphisms (SNPs) in PEAR1.Methods: In 582 consecutive patients with stable coronary artery disease (CAD) or acute coronary syndrome (ACS) scheduled for PCI and treated with ASA and Clopidogrel, Prasugrel, or Ticagrelor, SNP analysis for rs12566888, rs2768759, rs41273215, rs3737224, and rs822442 was performed. During a follow-up period of 365 days after initial PCI, all patients were tracked for a primary endpoint, defined as a combined endpoint consisting of either time to death, myocardial infarction (MI) or ischemic stroke. All cause mortality, MI and ischemic stroke were defined as secondary endpoints.Results: Multivariable Cox model analysis for the primary endpoint revealed a significantly increased risk in homozygous PEAR1 rs2768759 minor allele carriers (hazard ratio, 3.16; 95% confidence interval, 1.4–7.13, p = 0.006). Moreover, PEAR1 rs12566888 minor allele carriers also showed an increased risk in all patients (hazard ratio, 1.69; 95% confidence interval, 0.87–3.27, p = 0.122), which was marginally significant in male patients (hazard ratio, 2.12; 95% confidence interval, 1.02–4.43, p = 0.045; n = 425).Conclusions: To the best of our knowledge, this is the first study showing that distinct genetic variants of PEAR1 are associated with cardiovascular prognosis in high risk patients undergoing PCI and treated with dual anti platelet therapy.

Background: The role of genetic polymorphisms is important in defining the patient's prognosis and outcomes in coronary artery disease. The present study aimed to explore the association between platelet endothelial aggregation receptor 1 (PEAR1) rs12041331 polymorphism and the outcomes in patients with acute ischemic stroke treated with aspirin or dual antiplatelet therapy (DAPT) with clopidogrel.Methods: A total of 868 ischemic stroke patients admitted to our hospital from January 1, 2016 to December 30, 2018 were retrospectively studied. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification defined stroke subtypes. These patients were treated with aspirin alone or DAPT. The genotype distribution of PEAR1 rs12041331 single-nucleotide polymorphism (AA, AC, and CC) between different TOAST subtypes and treatment groups was assessed, and the clinical impact of genetic variants on functional outcomes defined by the National Institutes of Health Stroke Scale, modified Rankin Scale, and Barthel Index was analyzed using univariate and multivariate logistic regression models.Results: Among the 868 stroke patients, the PEAR1 AA genotype was 16%, GA was 47%, and GG was 36%. Forty-four percent had aspirin alone, and 56% had DAPT. Overall, the distribution of PEAR single-nucleotide polymorphism was not significant among the two treatment groups or subtypes of TOAST. In contrast, in patients treated with aspirin alone, PEAR1 AA tended to be higher in the small-artery occlusion (SAO) subtype when compared with the no-lacunar subtype, including cardioembolism and large-artery atherosclerosis. PEAR1 AA genotype was significantly associated with favorable functional outcomes at day 7 and discharge only in SAO patients treated with aspirin alone compared with the GG genotype. Multivariate regression models further suggested that AA genotype was independently associated with favorable outcomes in this group after being adjusted for three common stroke risk factors such as age, hypertension history, and C-reactive protein level [odds ratio (OR) 0.23, 95% confidence interval (CI), 0.07–0.64, P = 0.02 for 7-day National Institutes of Health Stroke Scale; OR 0.2, 95% CI, 0.06–0.66, P = 0.03 for 7-day modified Rankin Scale, and OR 0.25, 95% CI, 0.08–0.72, P = 0.03 for 7-day Barthel Index, respectively].Conclusion: The impact of PEAR1 rs12041331 polymorphism on aspirin depends on the TOAST subtype. PEAR1 AA carrier with SAO stroke is most sensitive to aspirin therapy. PEAR1 AA is an independent factor for the short-term functional outcomes in SAO patients treated with aspirin alone.Clinical Registration Number: 1800019911.

The influence of citrate concentrations on PFA-100 closure times, platelet hyper-reactivity and aspirin monitoring

Monitor Antiplatelet Therapy Among Patients with Ischemic Stroke By Platelet Function Assay-200 (PFA-200)

Platelet endothelial aggregation receptor 1 (PEAR1) may affect platelet-platelet contact and aggregation. The aim of this study was to assess the association between PEAR1 polymorphisms and risks of platelet aggregation. We searched the PubMed, EmBase, and Cochrane Library electronic databases for articles published through November 30th. 2016. Meta-analysis was performed to examine the relationship between PEAR1 and platelet aggregation and sensitivity analysis by removing individual study from meta-analysis. We collected and analyzed the results of 5 trials involving 5466 patients. Our results demonstrated that the G allele of rs12041331 was associated with a greater platelet aggregation by multiple agonists, both in the presence and absence of antiplatelet drugs, in several separate cohorts of different ethnicities along with an apparent allelic dose-response effect. However, the results of studies on rs2768759 locus were inconsistent and further studies are required. In the presence or absence of antiplatelet drugs treatment, the lowest platelet aggregation was observed in rs2768759 wild-type (AA) patients, followed by heterozygous (AC) and homozygous mutant (CC). PEAR1 rs12041331 is associated with platelet function and antiplatelet drug pharmacodynamics. Future studies on relationship between single nucleotide polymorphisms of PEAR1 and incidence of cardiovascular diseases are required.

Aspirin is a frequently prescribed drug for primary and secondary prevention of myocardial infarction, stroke and cardiovascular death. However, aspirin resistance may affect up to 45% of the population. Little is known on the role of genetic factors that contribute to resistance or augmented response to aspirin in different human populations. In a large sample of nonsmoker, medication-free healthy volunteers from mainland China (n = 323; age: 22.1 +/- 2.0 years) (mean +/- standard deviation), we determined the frequency of polymorphisms in cyclooxygenase 1 (COX1) (A-842G and C50T), glycoprotein IIIa (GPIIIa) (PLA1/A2) and purinergic receptor P2Y (P2Y1) (C893T and A1622G) genes. These candidate genes were chosen on the basis of their impact on platelet physiology and aspirin mode of action. A four panel P2Y1 genotype-stratified sample of healthy volunteers (n = 24 in total), identified from the large study sample above, prospectively received a 100 mg daily oral dose of aspirin for 7 days. We measured changes in platelet aggregation before and after aspirin treatment. As a comparison reference group, 6 out of 24 subjects in the prospective aspirin trial had the P2Y1 CT893/AG1622 genotype that displays a low frequency (<7%) in the Chinese population. COX1 A-842G, C50T and GPIIIa PLA1/A2 genetic polymorphisms were not observed in our sample from mainland China. Allele frequencies of P2Y1 893T and 1622G were 3.5 and 30.6%, respectively. The heterozygosity for the P2Y1 A1622G polymorphism observed in the present study was different to Caucasians; Chinese displayed a higher allele frequency for the 1622G allele. After aspirin treatment, the net decrease in arachidonic acid-induced platelet aggregation was significantly larger in the P2Y1 CT893/AG1622 genotype panel (83.4 +/- 3.7%, net reduction by aspirin expressed as percentage of baseline) compared with CC893/GG1622 (68.2 +/- 13.5%), CC893/AG1622 (68.9 +/- 9.6%) and CC893/AA1622 (65.1 +/- 9.1%) genotypic groups (p = 0.012, 0.025 and 0.004, respectively; statistical power = 77%). There was no significant difference in antiplatelet effect of aspirin among the CC893/GG1622, CC893/AG1622 and CC893/AA1622 genotypes (p > 0.05). The COX1 A-842G, C50T and GPIIIa PLA1/A2 polymorphisms are rare in Chinese. In contrast to previous studies in Caucasian populations, these candidate functional polymorphisms are unlikely to be significant contributors to aspirin pharmacodynamics in Chinese persons. Importantly, the presence of the P2Y1 893CC genotype appears to confer an attenuated antiplatelet effect during aspirin treatment in healthy Chinese volunteers. These data collectively underscore the importance of population-to-population variability in clinical pharmacogenetics research and provide a basis for further long-term studies of aspirin response and P2Y1 genetic variation in patients with cardiovascular risk.