Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel.
BACKGROUND
There is wide variability in the responses of individual patients to aspirin and clopidogrel. Polymorphisms of several platelet receptors have been related to increased platelet aggregation. We therefore aimed to evaluate whether these polymorphisms are related to altered response to aspirin or clopidogrel.


METHODS
Patients (n=120) undergoing percutaneous coronary intervention who received aspirin for > or =1 week but not clopidogrel were included. Blood samples were drawn at baseline and 20-24h after a 300-mg clopidogrel dose. Aspirin insensitivity was defined as 5 microM ADP-induced aggregation > or =70% and 0.5 mg/mL arachidonic acid-induced aggregation > or =20%. Clopidogrel insensitivity was defined as baseline minus post-treatment aggregation < or =10% in response to 5 and 20 microM ADP. PlA polymorphism of glycoprotein IIIa, T744C polymorphism of the P2Y(12) gene and the 1622A>G polymorphism of the P2Y(1) gene were genotyped by polymerase chain reaction.


RESULTS
There were no differences in polymorphism frequencies between drug-insensitive vs. drug-sensitive patients. There were also no significant differences in response to aspirin (assessed by arachidonic acid-induced aggregation) or to clopidogrel (assessed by ADP-induced aggregation or activation markers) when patients were grouped according to genotype. The only trend observed was lower reduction in PAC-1 binding following clopidogrel in PlA(2) carriers (P=0.065).


CONCLUSIONS
We did not find an association between polymorphisms in the platelet receptors GP IIIa, P2Y(12) or P2Y(1) and response to aspirin or clopidogrel in cardiac patients. These findings suggest that the variability in response to anti-platelet drugs is multi-factorial and is not caused only by single gene mutations.
The Methodist DeBakey Heart Center, The Methodist Hospital and Baylor College of Medicine, Section of Cardiology, 6565 Fannin St./Mail Station F-1090, Houston, TX 77030, USA.
Eli I
EI
Lev
Rajnikant T
RT
Patel
Sasidhar
S
Guthikonda
David
D
Lopez
Paul F
PF
Bray
Neal S
NS
Kleiman
D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D001241:Aspirin / Q000008:administration & dosage*; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011110:Polymorphism, Genetic; D018048:Receptors, Purinergic P2 / Q000235:genetics* / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
C061248:ITGB3 protein, human; D039661:Integrin beta3; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin