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


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 α2A-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.
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Aaron J
AJ
Peace
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Fabio
F
Mangiacapra
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Els
E
Bailleul
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Leen
L
Delrue
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Karen
K
Dierickx
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Micaela
M
Conte
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Etienne
E
Puymirat
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Anne Lies
AL
Fraeymans
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Pieter
P
Meeus
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Jozef
J
Bartunek
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).
Massimo
M
Volpe
From the Cardiovascular Center Aalst (A.J.P., F.M., L.D., K.D., M.C., E.P., J.B., E. Barbato) and Department of Haematology (E. Bailleul, A.L.F., P.M.), OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy (M.V.); and IRCCS Neuromed, Pozzilli, Italy (M.V.). emanuele.barbato@olvz-aalst.be.
Emanuele
E
Barbato
D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001792:Blood Platelets / Q000502:physiology*; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D058925:Receptors, Purinergic P2Y12 / Q000502:physiology
C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D058925:Receptors, Purinergic P2Y12; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D004837:Epinephrine
CYP2C19, human; adrenergic alpha-2A receptors; coronary artery disease; genetic polymorphism; platelet aggregation