α2A-adrenergic receptor polymorphism potentiates platelet reactivity in patients with stable coronary artery disease carrying the cytochrome P450 2C19*2 genetic variant

Aaron J. Peace, Fabio Mangiacapra, Els Bailleul, Leen Delrue, Karen Dierickx, Micaela Conte, Etienne Puymirat, Anne Lies Fraeymans, Pieter Meeus, Jozef Bartunek, Massimo Volpe, Emanuele Barbato

Research output: Contribution to journalArticle

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Abstract

Objective-Platelet α2A-adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation. The 6.3-kb variant of α2A-AR gene is associated with increased epinephrine-induced platelet aggregation in healthy volunteers. The cytochrome P450 2C19*2 (CYP2C19*2) loss-of-function allele influences P2Y12-mediated platelet inhibition and hence the rate of major adverse cardiovascular events. We assessed the influence of 6.3-kb α2A-AR gene variant on platelet aggregation and its interaction with CYP2C19*2 loss-of-function allele in patients with stable angina on aspirin and clopidogrel (dual antiplatelet therapy). Approach and Results-Aggregation to 5 increasing doses of epinephrine (from 0.156 to 10 μmol/L) was assessed in aggregation units by Multiplate Analyzer and platelet reactivity in P2Y12 reactivity units and % inhibition by VerifyNow P2Y12 assay before percutaneous revascularization. Gene polymorphisms were analyzed with TaqMan Drug Metabolism assay. Of 141 patients, aggregation was higher in 6.3-kb carriers (n=52) when compared with wild types (n=89) at all epinephrine doses (P2A-AR carriers. Percentage inhibition was lower (P=0.005) and P2Y12 reactivity units was higher (P=0.012) in CYP2C19*2 allele carriers. Higher P2Y12 reactivity units (P=0.037) and lower percentage inhibition (P=0.009) were observed in carriers of both 6.3-kb α2A-AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own. Conclusions-The 6.3-kb α2A-AR variant is associated with increased platelet reactivity to epinephrine and has an additive effect along with CYP2C19*2 loss-of-function allele on P2Y12-mediated platelet responses in patients with stable angina on dual antiplatelet therapy.

Original languageEnglish
Pages (from-to)1314-1319
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume34
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

Cytochrome P-450 Enzyme System
Adrenergic Receptors
Coronary Artery Disease
Blood Platelets
Alleles
Epinephrine
Platelet Aggregation
Stable Angina
clopidogrel
Genes
Aspirin
Healthy Volunteers
Mutation
Therapeutics
Pharmaceutical Preparations

Keywords

  • adrenergic alpha-2A receptors
  • coronary artery disease
  • CYP2C19, human
  • genetic polymorphism
  • platelet aggregation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

α2A-adrenergic receptor polymorphism potentiates platelet reactivity in patients with stable coronary artery disease carrying the cytochrome P450 2C19*2 genetic variant. / Peace, Aaron J.; Mangiacapra, Fabio; Bailleul, Els; Delrue, Leen; Dierickx, Karen; Conte, Micaela; Puymirat, Etienne; Fraeymans, Anne Lies; Meeus, Pieter; Bartunek, Jozef; Volpe, Massimo; Barbato, Emanuele.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 34, No. 6, 2014, p. 1314-1319.

Research output: Contribution to journalArticle

Peace, Aaron J. ; Mangiacapra, Fabio ; Bailleul, Els ; Delrue, Leen ; Dierickx, Karen ; Conte, Micaela ; Puymirat, Etienne ; Fraeymans, Anne Lies ; Meeus, Pieter ; Bartunek, Jozef ; Volpe, Massimo ; Barbato, Emanuele. / α2A-adrenergic receptor polymorphism potentiates platelet reactivity in patients with stable coronary artery disease carrying the cytochrome P450 2C19*2 genetic variant. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2014 ; Vol. 34, No. 6. pp. 1314-1319.
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abstract = "Objective-Platelet α2A-adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation. The 6.3-kb variant of α2A-AR gene is associated with increased epinephrine-induced platelet aggregation in healthy volunteers. The cytochrome P450 2C19*2 (CYP2C19*2) loss-of-function allele influences P2Y12-mediated platelet inhibition and hence the rate of major adverse cardiovascular events. We assessed the influence of 6.3-kb α2A-AR gene variant on platelet aggregation and its interaction with CYP2C19*2 loss-of-function allele in patients with stable angina on aspirin and clopidogrel (dual antiplatelet therapy). Approach and Results-Aggregation to 5 increasing doses of epinephrine (from 0.156 to 10 μmol/L) was assessed in aggregation units by Multiplate Analyzer and platelet reactivity in P2Y12 reactivity units and {\%} inhibition by VerifyNow P2Y12 assay before percutaneous revascularization. Gene polymorphisms were analyzed with TaqMan Drug Metabolism assay. Of 141 patients, aggregation was higher in 6.3-kb carriers (n=52) when compared with wild types (n=89) at all epinephrine doses (P2A-AR carriers. Percentage inhibition was lower (P=0.005) and P2Y12 reactivity units was higher (P=0.012) in CYP2C19*2 allele carriers. Higher P2Y12 reactivity units (P=0.037) and lower percentage inhibition (P=0.009) were observed in carriers of both 6.3-kb α2A-AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own. Conclusions-The 6.3-kb α2A-AR variant is associated with increased platelet reactivity to epinephrine and has an additive effect along with CYP2C19*2 loss-of-function allele on P2Y12-mediated platelet responses in patients with stable angina on dual antiplatelet therapy.",
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AU - Peace, Aaron J.

AU - Mangiacapra, Fabio

AU - Bailleul, Els

AU - Delrue, Leen

AU - Dierickx, Karen

AU - Conte, Micaela

AU - Puymirat, Etienne

AU - Fraeymans, Anne Lies

AU - Meeus, Pieter

AU - Bartunek, Jozef

AU - Volpe, Massimo

AU - Barbato, Emanuele

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N2 - Objective-Platelet α2A-adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation. The 6.3-kb variant of α2A-AR gene is associated with increased epinephrine-induced platelet aggregation in healthy volunteers. The cytochrome P450 2C19*2 (CYP2C19*2) loss-of-function allele influences P2Y12-mediated platelet inhibition and hence the rate of major adverse cardiovascular events. We assessed the influence of 6.3-kb α2A-AR gene variant on platelet aggregation and its interaction with CYP2C19*2 loss-of-function allele in patients with stable angina on aspirin and clopidogrel (dual antiplatelet therapy). Approach and Results-Aggregation to 5 increasing doses of epinephrine (from 0.156 to 10 μmol/L) was assessed in aggregation units by Multiplate Analyzer and platelet reactivity in P2Y12 reactivity units and % inhibition by VerifyNow P2Y12 assay before percutaneous revascularization. Gene polymorphisms were analyzed with TaqMan Drug Metabolism assay. Of 141 patients, aggregation was higher in 6.3-kb carriers (n=52) when compared with wild types (n=89) at all epinephrine doses (P2A-AR carriers. Percentage inhibition was lower (P=0.005) and P2Y12 reactivity units was higher (P=0.012) in CYP2C19*2 allele carriers. Higher P2Y12 reactivity units (P=0.037) and lower percentage inhibition (P=0.009) were observed in carriers of both 6.3-kb α2A-AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own. Conclusions-The 6.3-kb α2A-AR variant is associated with increased platelet reactivity to epinephrine and has an additive effect along with CYP2C19*2 loss-of-function allele on P2Y12-mediated platelet responses in patients with stable angina on dual antiplatelet therapy.

AB - Objective-Platelet α2A-adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation. The 6.3-kb variant of α2A-AR gene is associated with increased epinephrine-induced platelet aggregation in healthy volunteers. The cytochrome P450 2C19*2 (CYP2C19*2) loss-of-function allele influences P2Y12-mediated platelet inhibition and hence the rate of major adverse cardiovascular events. We assessed the influence of 6.3-kb α2A-AR gene variant on platelet aggregation and its interaction with CYP2C19*2 loss-of-function allele in patients with stable angina on aspirin and clopidogrel (dual antiplatelet therapy). Approach and Results-Aggregation to 5 increasing doses of epinephrine (from 0.156 to 10 μmol/L) was assessed in aggregation units by Multiplate Analyzer and platelet reactivity in P2Y12 reactivity units and % inhibition by VerifyNow P2Y12 assay before percutaneous revascularization. Gene polymorphisms were analyzed with TaqMan Drug Metabolism assay. Of 141 patients, aggregation was higher in 6.3-kb carriers (n=52) when compared with wild types (n=89) at all epinephrine doses (P2A-AR carriers. Percentage inhibition was lower (P=0.005) and P2Y12 reactivity units was higher (P=0.012) in CYP2C19*2 allele carriers. Higher P2Y12 reactivity units (P=0.037) and lower percentage inhibition (P=0.009) were observed in carriers of both 6.3-kb α2A-AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own. Conclusions-The 6.3-kb α2A-AR variant is associated with increased platelet reactivity to epinephrine and has an additive effect along with CYP2C19*2 loss-of-function allele on P2Y12-mediated platelet responses in patients with stable angina on dual antiplatelet therapy.

KW - adrenergic alpha-2A receptors

KW - coronary artery disease

KW - CYP2C19, human

KW - genetic polymorphism

KW - platelet aggregation

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