Department of Clinical Pharmacology, Royal College of Surgeons, Dublin, Ireland.
J Thromb Haemost. 2010 May;8(5):934-41. doi: 10.1111/j.1538-7836.2010.03775.x. Epub 2010 Jan 22.
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.
To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist.
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.
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).
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.
血小板对抗血小板药物反应的变异性是可遗传的。G 蛋白β多肽 3（GNB3）基因中的一个常见单碱基替换（825C>T）导致人类 G 蛋白β3（Gbeta3）亚单位的选择性剪接（41 个氨基酸缺失）。这种由 GNB3 T 等位基因携带者携带的截断蛋白与冠状动脉疾病有关，并被认为是药物反应的遗传标志物。对高加索人群的大型研究表明，T 等位基因携带者的血小板反应性较低。
评估 GNB3 基因型是否会使接受 GPIIb/IIIa 受体拮抗剂治疗的患者易发生出血。
在不稳定型冠状动脉综合征-心肌梗死溶栓治疗（OPUS-TIMI）16 基因亚研究的患者中，确定了 orbofiban 治疗患者 DNA 样本中的 GNB3 基因型分布。在治疗和安慰剂组中，估计基因型对出血终点和死亡、心肌梗死（MI）、缺血再住院和紧急血运重建的复合主要终点的影响。
在 887 名患者中，45.1%携带 GNB3 CC 基因型，44.5%携带 CT 基因型，10.4%携带 TT 基因型。T 等位基因携带者与治疗出血之间的相互作用具有统计学意义（P = 0.008）。这反映了这样一个事实，即与安慰剂相比，接受 orbofiban 治疗的 GNB3 非-T 携带者没有出血作用（RR = 0.92，95%CI 0.55-1.55），而 T 携带者则有（RR = 2.62，95%CI 1.58-4.35，P < 0.001）。T 等位基因携带者与治疗之间的相互作用对主要终点（P = 0.18）或 MI（P = 0.69）无统计学意义。
GNB3 T 等位基因显著增加了接受血小板拮抗剂 orbofiban 治疗的患者的出血风险。我们的发现表明，与抗血小板药物相关的出血风险是可遗传的，并且可能与血栓形成风险无关。
