G-protein beta3 subunit polymorphism and bleeding in the orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16 trial.
BACKGROUND
Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein beta3 (Gbeta3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity.


OBJECTIVE
To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist.


METHODS
GNB3 genotype distribution was determined in DNA samples from patients in the orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction (OPUS-TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm.


RESULTS
Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55-1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58-4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69).


CONCLUSIONS
The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.
Maree
A O
AO
Department of Clinical Pharmacology, Royal College of Surgeons, Dublin, Ireland. andrew.maree@gmail.com
Vangjeli
C
C
Jneid
H
H
Ryan
J
J
Cox
D
D
Cannon
C P
CP
Shields
D C
DC
Fitzgerald
D J
DJ
D000409:Alanine / Q000627:therapeutic use; D006331:Heart Diseases / Q000188:drug therapy* / Q000235:genetics; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D011110:Polymorphism, Genetic; D011759:Pyrrolidines / Q000627:therapeutic use*; D015912:Thrombolytic Therapy
C454420:G-protein beta3 subunit; D011759:Pyrrolidines; D020962:Heterotrimeric GTP-Binding Proteins; C120234:orbofiban; D000409:Alanine