Abstract 4002: G-Protein Beta3 Subunit Polymorphism (GNB3 825T) Carriage is Associated with Increased Bleeding in the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction (OPUS-TIMI) 16 Trial
Variability in platelet response to antiplatelet drugs is heritable and differs between sexes. 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 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. We hypothesized that GNB3 genotype would modulate response to the oral GPIIb/IIIa receptor antagonist orbofiban in patients with acute coronary syndromes. GNB3 genotype distribution was determined in DNA samples from patients in the OPUS-TIMI 16 genetic sub-study. Impact of genotype on the composite primary endpoint of death, MI, rehospitalization for ischemia and urgent revascularization and the bleeding endpoint was estimated in the treatment and placebo arm. Of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T-allele carriership and treatment was not significant for the primary endpoint (p=0.18) or myocardial infarction (p=0.69). However, 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 to placebo (RR=0.92, 95% CI 0.55–1.55) while T-carriers did (RR=2.62, 95% CI 1.58 – 4.35, p<0.001). The bleeding association appeared more significant in females than males (RR=4.24, 95% CI 1.60 –11.24, P=0.004 vs. RR=2.09, 95% CI 1.15–3.79, p=0.01 for either orbofiban dose and RR=5.51, 95% CI 1.99 –15.25, P=0.001 vs. RR =2.32, 95% CI 1.20 – 4.49, P=0.01 for the higher dose respectively). 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.