Genetic determinants of on-aspirin platelet reactivity: focus on the influence of PEAR1

Morten Würtz, Peter H Nissen, Erik Lerkevang Grove, Steen Dalby Kristensen, Anne-Mette Hvas, Morten Würtz, Peter H Nissen, Erik Lerkevang Grove, Steen Dalby Kristensen, Anne-Mette Hvas

Abstract

Background: 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.

Aim: To 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.

Methods: We 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.

Results: The 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.

Conclusion: A 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 registration: ClinicalTrials.gov NCT01383304.

Conflict of interest statement

Competing Interests: AMH has received speaker honoraria and financial support for scientific purposes from CSL Bering, Leo Pharma, and Octapharma. ELG has received speaker honoraria from AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Pfizer and Sysmex, and has participated in advisory board meetings for AstraZeneca, Bayer, and Bristol-Myers Squibb. SDK is supported by a research fellowship from the Novo Nordisk Foundation and has received speaker honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Iroko, Pfizer, and The Medicines Company. MW and PHN report no conflicts of interest. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Association of PEAR1 rs12041331 genotype…
Figure 1. Association of PEAR1 rs12041331 genotype with on-aspirin platelet aggregation assessed by multiple electrode aggregometry (Multiplate Analyzer) and VerifyNow Aspirin.
Comparisons of platelet aggregation levels across genotypes were adjusted for the following baseline variables and cardiovascular risk factors: Age, sex, smoking, body mass index, previous myocardial infarction, diabetes, proton pump inhibitor use, and platelet count. Patients homozygous for the A allele were pooled with heterozygotes for regression analysis. Horizontal lines and boxes indicate median with interquartile range. Whiskers indicate ±1.5 interquartile range and points beyond whiskers indicate outliers.

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