Impact of Platelet Endothelial Aggregation Receptor-1 Genotypes on Long-Term Cerebrovascular Outcomes in Patients With Minor Stroke or Transient Ischemic Attack

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Impact of Platelet Endothelial Aggregation Receptor-1 Genotypes on Long-Term Cerebrovascular Outcomes in Patients With Minor Stroke or Transient Ischemic Attack

Xiao-Guang Zhang^†, Jing-Yu Gu^†, Qiang-Qiang Fu^†, Shi-Wu Chen, Jie Xue, Shan-Shan Jiang, Yu-Ming Kong, You-Mei Li^* and Yun-Hua Yue^*

• Department of Neurology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China

Background: Platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 has been reported to affect agonist-stimulated platelet aggregation, but it remains unclear whether this variant plays a role in recurrent stroke. Here we assess the clinical relevance of PEAR1 rs12041331 in acute minor ischemic stroke (AMIS) and transient ischemic attack (TIA) Chinese patients treated with dual antiplatelet therapy (DAPT).

Methods: We recruited 273 consecutive minor stroke and TIA patients, and Cox proportional hazard regression was used to model the relationship between PEAR1 rs12041331 and thrombotic and bleeding events.

Results: Genotyping for PEAR1 rs12041331 showed 49 (18.0%) AA homozygotes, 129 (47.3%) GA heterozygotes, and 95 (34.7%) GG homozygotes. No association was observed between PEAR1 rs12041331 genotype and stroke or composite clinical vascular event rates (ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, or vascular death) or bleeding events regardless if individuals carried one or two copies of the A allele. Our results suggested that rs12041331 genetic polymorphism was not an important contributor to clinical events in AMIS and TIA patients in the setting of secondary prevention.

Conclusions: Our data do provide robust evidence that genetic variation in PEAR1 rs12041331 do not contribute to atherothrombotic or bleeding risk in minor stroke and TIA patients treated with DAPT.

Introduction

Patients with acute minor ischemic stroke (AMIS) and transient ischemic attack (TIA) have a high risk of recurrent stroke and cardiovascular events (1). Current guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and clopidogrel as a standard of care for patients with AMIS and TIA who can be treated within 24 h after the onset of symptoms (2, 3). However, CHANCE trial reported that up to 8.2% of patients receiving DAPT still experienced a recurrent stroke (2). Antiplatelet drug resistance was found to contribute to recurrent stroke (4, 5), which may be associated with many potential genetic and environmental factors (6). However, the correlation between genetic polymorphisms and recurrent stroke is not yet fully elaborated.

Platelet endothelial aggregation receptor-1 (PEAR1) is a platelet transmembrane tyrosine kinase receptor involved in platelet–platelet contact and platelet aggregation, which is highly expressed in platelets and endothelium (7). Studies have shown that genetic variants in the PEAR1 gene were not only associated with platelet aggregation (8, 9) but also the response to antiplatelet agents including aspirin (10) and clopidogrel (11). Rs12041331 is an intronic variant that is supposed to modify PEAR1 expression in the protein level via a different allele-specific DNA methylation and has been found to be correlated with platelet aggregation (12, 13). Although there has been evidence that PEAR1 rs12041331 has an effect on agonist-stimulated platelet aggregation in aspirin-treated patients (14), it is still controversial whether this genetic polymorphism in PEAR1 is associated with clinical outcomes. Xu et al. reported that PEAR1 rs12041331 plays an important role in early cardiovascular outcomes in patients undergoing percutaneous coronary intervention in a Chinese population (15). However, in a white population, Yang et al. could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications (16). Currently, research on the relationship between PEAR1 rs12041331 and the clinical events were mainly focused on coronary heart diseases. In a retrospective, case–control study, the A allele showed a higher frequency than the G allele in the recurrent ischemic stroke group (17). However, there has been no study on the relationship between PEAR1 polymorphism and the long-term cerebrovascular events in patients with minor stroke and TIA.

To assess the clinical relevance of PEAR1 rs12041331 in Chinese AMIS and TIA patients treated with DAPT, we investigated the prevalence of PEAR1 rs12041331 genotypes and estimated its association with long-term cerebrovascular events, bleeding events, and clinical function.