Effect of Genetic Polymorphism Including NUP153 and SVEP1 on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects
Effect of Genetic Polymorphism Including NUP153 and SVEP1 on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects
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NUP153和SVEP1基因多态性对中国健康受试者替格瑞洛药动学和药效学的影响
DOI：
10.1007/s40261-022-01154-6
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Yimin Cui
中科院分区：
文献类型：
--
作者：
Qian Xiang;Zhiyan Liu;Guangyan Mu;Qiufen Xie;Hanxu Zhang;Shuang Zhou;Zining Wang;Ninghong Guo;Jie Huang;Jie Jiang;Jian Li;Guoping Yang;Yimin Cui
寻找影响替格瑞洛药效学和药代动力学的潜在基因位点引起了广泛的临床兴趣。本研究的目的是探讨基因多态性对中国健康受试者替格瑞洛药代动力学和药效学的影响。这是一项在中国的多中心研究，包括北京、南昌和长沙的三家医院。年龄 18-45 岁、基因型未知的健康中国受试者被纳入。所有受试者均接受单次口服剂量 90 毫克替格瑞洛。评估了血浆样品中替格瑞洛及其主要活性代谢物的血小板聚集和浓度-时间曲线下面积。进行了与替格瑞洛相关的全基因组关联研究和候选基因关联分析。招募并完成了 175 名中国本土受试者。根据p值，替格瑞洛群体的阈值为6.57×10-7（0.05/76106），基因NUP153的1个单核苷酸多态性chr6：17616513（p = 2.03×10-7）与零时血浆浓度与最后可测量时间点的浓度-时间曲线下面积相关，以及1个单核苷酸 鉴定出与替格瑞洛P2Y12反应单元12h相关的SVEP1基因rs17204533多态性(p=3.96×10-7)。此外，L1TD1、CETP、CLEC2A、CHSY1、PDZRN3、CTU2、PIEZO1、APOBEC1、SEMA6A、KAZN和FASN多态性可能影响替格瑞洛的药代动力学，而PARP10、TRIB1、CYP2C19和UGT2B7可能影响其药效学。遗传变异影响替格瑞洛的药代动力学。 替格瑞洛在健康个体中的药代动力学和药效学。 NUP153、SVEP1基因变异的检测将有助于药效预测和评价，这些基因的调控可能成为新药开发的目标。需要进一步的研究来证实结果并探讨这些单核苷酸多态性是否仅与血小板活性相关，或者还与心血管事件和全因死亡率相关。NCT03161002。
The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese subjects.This is a multi-center study in China, including three hospitals from Beijing, Nanchang, and Changsha. Healthy Chinese subjects aged 18-45 years with unknown genotypes were included. All subjects received a single oral dose of 90 mg of ticagrelor. Platelet aggregation and the area under the concentration-time curve for ticagrelor and its major active metabolite in plasma samples were assessed. Genome-wide association studies and candidate gene association analysis related to ticagrelor were performed.One hundred and seventy-five native Chinese subjects were enrolled and completed the study. According to the p value, the threshold of ticagrelor population was 6.57 × 10-7 (0.05/76106), one single-nucleotide polymorphism chr6:17616513 of gene NUP153 (p = 2.03 × 10-7) related to the area under the concentration-time curve for plasma concentration at time zero versus the last measurable timepoint, and one single nucleotide polymorphism rs17204533 of gene SVEP1 (p = 3.96 × 10-7) related to P2Y12 reaction unit12h of ticagrelor was identified. In addition, L1TD1, CETP, CLEC2A, CHSY1, PDZRN3, CTU2, PIEZO1, APOBEC1, SEMA6A, KAZN, and FASN polymorphisms might influence the pharmacokinetics of ticagrelor, while PARP10, TRIB1, CYP2C19, and UGT2B7 might affected its pharmacodynamics.Genetic variation affects the pharmacokinetics and pharmacodynamics of ticagrelor in healthy individuals. The detection of NUP153, SVEP1 gene variation will be helpful for pharmacodynamic prediction and evaluation, and the regulation of these genes may be the target of new drug development. Further studies are required to confirm the results and explore whether these single-nucleotide polymorphisms are associated only with platelet activity or also with cardiovascular events and all-cause mortality.NCT03161002.
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影响因子：
5.6
作者：
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通讯作者：
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作者：
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