α 2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant

Abstract

Objective— Platelet α 2A -adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation. The 6.3-kb variant of α 2A -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 α 2A -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 ( P <0.05) apart from 10 μmol/L ( P =0.077). Percentage inhibition was lower ( P =0.048) in 6.3-kb α 2A -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 α 2A -AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own. Conclusions— The 6.3-kb α 2A -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.