Backman Joshua D, O'Connell Jeffrey R, Tanner Keith, Peer Cody J, Figg William D, Spencer Shawn D, Mitchell Braxton D, Shuldiner Alan R, Yerges-Armstrong Laura M, Horenstein Richard B, Lewis Joshua P
aSchool of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore bGeriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore cClinical Pharmacology Program, National Cancer Institute, Bethesda dApplied and Developmental Research, SAIC-Frederick Inc., National Cancer Institute, Frederick, Maryland, USA.
Pharmacogenet Genomics. 2017 Apr;27(4):159-163. doi: 10.1097/FPC.0000000000000272.
Clopidogrel is one of the most commonly used therapeutics for the secondary prevention of cardiovascular events in patients with acute coronary syndromes. However, considerable interindividual variation in clopidogrel response has been documented, resulting in suboptimal therapy and an increased risk of recurrent events for some patients. In this investigation, we carried out the first genome-wide association study of circulating clopidogrel active metabolite levels in 513 healthy participants to directly measure clopidogrel pharmacokinetics. We observed that the CYP2C19 locus was the strongest genetic determinant of active metabolite formation (P=9.5×10). In addition, we identified novel genome-wide significant variants on chromosomes 3p25 (rs187941554, P=3.3×10) and 17q11 (rs80343429, P=1.3×10), as well as six additional loci that showed suggestive evidence of association (P≤1.0×10). Four of these loci showed nominal associations with on-clopidogrel ADP-stimulated platelet aggregation (P≤0.05). Evaluation of clopidogrel active metabolite concentration may help identify novel genetic determinants of clopidogrel response, which has implications for the development of novel therapeutics and improved antiplatelet treatment for at-risk patients in the future.
氯吡格雷是急性冠状动脉综合征患者心血管事件二级预防中最常用的治疗药物之一。然而，已有文献记载氯吡格雷反应存在相当大的个体差异，导致治疗效果欠佳，部分患者复发事件风险增加。在本研究中，我们对513名健康参与者进行了首次全基因组关联研究，以直接测量氯吡格雷的药代动力学，研究循环中氯吡格雷活性代谢物水平。我们观察到，CYP2C19基因座是活性代谢物形成的最强遗传决定因素（P = 9.5×10）。此外，我们在3号染色体p25区域（rs187941554，P = 3.3×10）和17号染色体q11区域（rs80343429，P = 1.3×10）鉴定出全基因组显著变异，以及另外六个显示出关联暗示证据的基因座（P≤1.0×10）。其中四个基因座与服用氯吡格雷时ADP刺激的血小板聚集存在名义上的关联（P≤0.05）。评估氯吡格雷活性代谢物浓度可能有助于识别氯吡格雷反应的新遗传决定因素，这对未来新型治疗药物的开发以及高危患者抗血小板治疗的改善具有重要意义。
