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.

Impact of genetic polymorphisms on platelet function and response to anti platelet drugs

“…Adrenergic receptors alpha and beta are both expressed on platelets surface. Even if epinephrine is a weak agonist, the variant 6.3 kb of the α 2A receptor determines an increased response and higher platelet reactivity in patients with CAD treated with dual antiplatelet therapy (DAPT) (16). The genetic variant of ADRA2B gene responsible for the deletion of three glutamate in the α 2B receptor gives resistance to down-regulation, resulting in a higher risk of acute coronary events.…”