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

Würtz M, Nissen PH, Grove EL, Kristensen SD, Hvas AM - PLoS ONE (2014)

Bottom Line: 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).Serum thromboxane B2 was measured to confirm aspirin adherence and was used as a marker of cyclooxygenase-1 activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Department of Internal Medicine, Regional Hospital West Jutland, Herning, Denmark.

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.

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Related in: MedlinePlus

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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pone-0111816-g001: 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.

Mentions: In Table 3, platelet aggregation levels are presented according to genotype for each SNP. Associations between aggregation levels and genotypes were assessed employing the Bonferroni-adjusted significance level of p<0.0011. Patients homozygous AA or heterozygous GA for the rs12041331 SNP displayed decreased on-aspirin platelet aggregation in response to arachidonic acid and collagen (Figure 1). The major difference was between the AA and GG genotypes and results were robust across platelet function tests, although the signal was stronger when using multiple electrode aggregometry compared to the VerifyNow Aspirin assay. None of the other 14 SNPs subjected to statistical analysis revealed any association with on-aspirin platelet aggregation that was consistent across platelet function tests or agonists.


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

Würtz M, Nissen PH, Grove EL, Kristensen SD, Hvas AM - PLoS ONE (2014)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216141&req=5

pone-0111816-g001: 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.
Mentions: In Table 3, platelet aggregation levels are presented according to genotype for each SNP. Associations between aggregation levels and genotypes were assessed employing the Bonferroni-adjusted significance level of p<0.0011. Patients homozygous AA or heterozygous GA for the rs12041331 SNP displayed decreased on-aspirin platelet aggregation in response to arachidonic acid and collagen (Figure 1). The major difference was between the AA and GG genotypes and results were robust across platelet function tests, although the signal was stronger when using multiple electrode aggregometry compared to the VerifyNow Aspirin assay. None of the other 14 SNPs subjected to statistical analysis revealed any association with on-aspirin platelet aggregation that was consistent across platelet function tests or agonists.

Bottom Line: 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).Serum thromboxane B2 was measured to confirm aspirin adherence and was used as a marker of cyclooxygenase-1 activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Department of Internal Medicine, Regional Hospital West Jutland, Herning, Denmark.

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.

Show MeSH
Related in: MedlinePlus