Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA.
Department of Internal Medicine, Béziers Hospital, 2 Rue Valentin Hau, BP 740, Béziers 34525, France.
Eur Heart J Cardiovasc Pharmacother. 2020 Jul 1;6(4):203-210. doi: 10.1093/ehjcvp/pvz045.
Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial.
We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C192, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C1917, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C92, P = 1.2 × 10-3; and CYP2C93, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles.
Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.
氯吡格雷用于预防动脉血栓栓塞事件。虽然研究已经确定了个体间治疗血小板抑制作用的变异性的遗传决定因素（例如 CYP2C19*2），但这些变体是否具有预测主要不良心血管事件（CVE）的临床实用性仍存在争议。
我们评估了 31 个候选基因多态性对 3391 例接受氯吡格雷治疗的冠状动脉疾病患者中腺苷二磷酸（ADP）刺激的血小板反应性的影响。在国际氯吡格雷药物基因组学联合会（ICPC）中，在 2134 例具有临床事件数据的患者（N=129 例事件）中测试了这些多态性对 CVE 的影响。几种变体与治疗中的 ADP 刺激的血小板反应性相关（CYP2C192，P=8.8×10-54；CES1 G143E，P=1.3×10-16；CYP2C1917，P=9.5×10-10；CYP2B6 1294+53C>T，P=3.0×10-4；CYP2B6 516G>T，P=1.0×10-3；CYP2C92，P=1.2×10-3；和 CYP2C93，P=1.5×10-3）。虽然没有个体变体与 CVE 相关，但药物基因组多基因反应评分（PgxRS）的生成表明，携带与治疗中血小板反应性增加相关的等位基因数量较多的患者更有可能经历 CVE（β=0.17，SE 0.06，P=0.01）和心血管相关死亡（β=0.43，SE 0.16，P=0.007）。携带 8 个或更多风险等位基因的患者发生 CVE 的可能性显著增加[比值比（OR）=1.78，95%置信区间（CI）1.14-2.76，P=0.01]和心血管死亡（OR=4.39，95%CI 1.35-14.27，P=0.01）与携带这些等位基因的患者相比。
几种多态性影响氯吡格雷的反应，而 PgxRS 是心血管结局的预测因子。进一步研究确定氯吡格雷反应的新决定因素并验证多基因模型可能有助于未来的精准医学策略。
