Genetic Variation in PEAR1 Is Associated With Platelet Aggregation and Cardiovascular Outcomes

Study Questions:

What genetic variants are associated with platelet response to dual antiplatelet therapy (DAPT) and cardiovascular (CV) outcomes?

Methods:

A genome-wide association study (GWAS) for drug response to DAPT was performed in 565 individuals. Significant findings were extended by examining genotype and CV outcomes in two independent aspirin-treated cohorts: 227 percutaneous coronary intervention (PCI) patients, and 1,000 patients of the International VErapamil SR/trandolapril Study (INVEST) GENEtic Substudy (INVEST-GENES).

Results:

GWAS revealed a strong association between single nucleotide polymorphisms on chromosome 1q23 and post-DAPT platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with DAPT response (p = 7.66 x 10–9). In Caucasian and African American patients undergoing PCI, A-allele carriers of rs12041331 were more likely to experience a CV event or death compared to GG homozygotes (hazard ratio [HR], 2.62; p = 0.059 and HR, 3.97; p = 0.035, respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared to GG homozygotes (odds ratio, 2.03; 95% confidence interval, 1.01-4.09; p = 0.048).

Conclusions:

The authors concluded that common genetic variation in PEAR1 may be a determinant of platelet response and CV events in patients on aspirin, alone and in combination with clopidogrel.

Perspective:

DAPT is standard therapy post-PCI and post–acute coronary syndrome. Platelet response to DAPT is variable between patients, and poor responders may be at increased risk for CV events. Identification of poor responders could allow adjustment of DAPT, especially if these adjustments were shown to improve outcomes. This GWAS identifies a candidate gene variant that may predict both platelet response and CV outcomes. The clinical utility of these findings will need to be evaluated.

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Statins, Interventions and ACS

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Platelet Function Tests, Genome-Wide Association Study, Ticlopidine, Percutaneous Coronary Intervention, Polymorphism, Single Nucleotide, Platelet Aggregation, Indoles, Verapamil, United States


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