Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, level 1, SE-751 85 Uppsala, Sweden
Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, level 1, SE-751 85 Uppsala, Sweden.
Eur Heart J. 2015 Aug 1;36(29):1901-12. doi: 10.1093/eurheartj/ehv116. Epub 2015 May 2.
Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial.
A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 × 10(-6)) and ARC (P = 4.6 × 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 × 10(-15) and rs56324128, P = 9.7 × 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 × 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea.
In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment.
NCT00391872.
替格瑞洛是一种直接作用的 P2Y12 受体拮抗剂，吸收迅速，部分代谢为主要代谢物 AR-C124910XX（ARC）。为了鉴定与替格瑞洛药代动力学和临床结局相关的单核苷酸多态性（SNP），我们在接受替格瑞洛治疗的 PLATO 试验患者中进行了全基因组关联研究（GWAS）。
采用两阶段设计进行 GWAS，包括发现阶段（n=1812）和复制阶段（n=1941）。通过群体药代动力学（PK）模型估算稳态 AUCss 值，并使用线性回归在全基因组范围内进行分析。在 4990 例患者中，使用 Cox 回归分析 SNP 与临床事件的关系。SLCO1B1 中的 SNP（rs113681054）与替格瑞洛（P=1.1×10(-6))和 ARC（P=4.6×10(-13))水平相关。该 SNP 与功能性变体（rs4149056）连锁不平衡，导致 OATP1B1 转运体活性降低。替格瑞洛水平还与 CYP3A4 区域中的两个独立 SNP（rs62471956，P=7.7×10(-15)和 rs56324128，P=9.7×10(-12))相关。此外，ARC 水平与 UGT2B7 中的 rs61361928 相关（P=3.0×10(-14))。在所有基因座中，效应均较小。影响替格瑞洛 PK 的鉴定 SNP 均与主要复合结局（心血管死亡、心肌梗死和卒中）、非 CABG 相关出血或研究者报告的呼吸困难无关。
在 ACS 患者中，替格瑞洛的药代动力学受三个遗传位点（SLCO1B1、UGT2B7 和 CYP3A4）影响。然而，替格瑞洛血浆水平的遗传效应较小，并未转化为替格瑞洛治疗期间疗效或安全性的任何可检测影响。
NCT00391872。
