Abstract
BackgroundPlatelet aggregation during aspirin treatment displays considerable inter-individual variability. A genetic etiology likely exists, but it remains unclear to what extent genetic polymorphisms determine platelet aggregation in aspirin-treated individuals.AimTo identify platelet-related single nucleotide polymorphisms (SNPs) influencing platelet aggregation during aspirin treatment. Furthermore, we explored to what extent changes in cyclooxygenase-1 activity and platelet activation may explain such influence.MethodsWe included 985 Danish patients with stable coronary artery disease treated with aspirin 75 mg/day mono antiplatelet therapy. Patients were genotyped for 16 common SNPs in platelet-related genes using standard PCR-based methods (TaqMan). Platelet aggregation was evaluated by whole blood platelet aggregometry employing Multiplate Analyzer (agonists: arachidonic acid and collagen) and VerifyNow Aspirin. Serum thromboxane B2 was measured to confirm aspirin adherence and was used as a marker of cyclooxygenase-1 activity. Soluble P-selectin was used as marker of platelet activation. Platelet aggregation, cyclooxygenase-1 activity, and platelet activation were compared across genotypes in adjusted analyses.ResultsThe A-allele of the rs12041331 SNP in the platelet endothelial aggregation receptor-1 (PEAR1) gene was associated with reduced platelet aggregation and increased platelet activation, but not with cyclooxygenase-1 activity. Platelet aggregation was unaffected by the other SNPs analyzed.ConclusionA common genetic variant in PEAR1 (rs12041331) reproducibly influenced platelet aggregation in aspirin-treated patients with coronary artery disease. The exact biological mechanism remains elusive, but the effect of this polymorphism may be related to changes in platelet activation. Furthermore, 14 SNPs previously suggested to influence aspirin efficacy were not associated with on-aspirin platelet aggregation.Clinical Trial RegistrationClinicalTrials.gov NCT01383304
Highlights
Low-dose aspirin substantially reduces the risk of recurrent arterial thrombosis [1], yet one fifth of aspirin-treated patients suffer recurrent cardiovascular events
The A-allele of the rs12041331 single nucleotide polymorphism (SNP) in the platelet endothelial aggregation receptor-1 (PEAR1) gene was associated with reduced platelet aggregation and increased platelet activation, but not with cyclooxygenase-1 activity
The exact biological mechanism remains elusive, but the effect of this polymorphism may be related to changes in platelet activation
Summary
Low-dose aspirin substantially reduces the risk of recurrent arterial thrombosis [1], yet one fifth of aspirin-treated patients suffer recurrent cardiovascular events. This may reflect that some patients do not derive adequate platelet inhibition from aspirin [1,2]. A biological basis for familial clustering of aspirin response phenotypes may exist, but delineating the specific genetic architecture that predisposes to reduced effect of aspirin remains challenging. Platelet aggregation during aspirin treatment displays considerable inter-individual variability. A genetic etiology likely exists, but it remains unclear to what extent genetic polymorphisms determine platelet aggregation in aspirin-treated individuals
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