CYP3A4/5、POR基因多态性与中国成年心脏移植受者他克莫司血药浓度相关性的研究

周红, 张菁, 伍三兰, 刘亚妮, 师少军, 张玉, 韩勇

中国药学杂志 ›› 2017, Vol. 52 ›› Issue (19) : 1710-1714.

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中国药学杂志 ›› 2017, Vol. 52 ›› Issue (19) : 1710-1714. DOI: 10.11669/cpj.2017.19.012
论著

CYP3A4/5、POR基因多态性与中国成年心脏移植受者他克莫司血药浓度相关性的研究

  • 周红1, 张菁2, 伍三兰1, 刘亚妮1, 师少军1, 张玉1, 韩勇1
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Associations of CYP3A4/5 and POR Polymorphisms with Tacrolimus Concentrations in Chinese Adult Heart Transplant Recipients

  • ZHOU Hong1, ZHANG Jing2, WU San-lan1, LIU Ya-ni1, SHI Shao-jun1, ZHANG Yu1, HAN Yong1
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摘要

目的 探讨CYP3A4/5和POR单核苷酸多态性(SNP)与中国成年心脏移植受者他克莫司剂量校正浓度(ρ0/D)的相关性,为制定该人群个体化剂量调整方案提供参考。方法 共纳入90例中国成年心脏移植术后早期的受者,采用焦磷酸测序法检测CYP3A4*1G GA(rs2242480),Sanger法检测CYP3A5*3 A>G(rs776746), POR*28 C>T(rs1057868),酶放大免疫测定法(EMIT)测定他克莫司血药谷浓度。分析上述基因型与ρ0/D、达靶浓度时间和达靶浓度所需剂量的相关性。结果 CYP3A4*1GCYP3A5*3POR*28等位基因频率均符合Hardy-Weinberg遗传平衡。CYP3A5*3/*3基因型心脏移植患者ρ0/D比*1/*1*1/*3携带者显著增加,达靶浓度时间显著缩短,达靶浓度所需剂量显著降低。CYP3A4*1/*1G等位基因携带者ρ0/D显著低于野生型。基于CYP3A5分层分析,在CYP3A5表达与不表达组中,CYP3A4和POR不同基因型均与他克莫司ρ0/D无相关性。POR*28/*28基因型受者达靶浓度时间显著延长。结论 中国成年心脏移植受者CYP3A4*1GCYP3A5*3基因型与他克莫司ρ0/D显著相关,移植前进行检测将有助于他克莫司的临床个体化用药。

Abstract

OBJECTIVE To investigate associations between CYP3A4/5 and POR single nucleotide polymorphisms(SNPs)and tacrolimus dose-corrected concentrations(ρ0/D) in Chinese adult heart transplant recipients, providing individualized dose-adjustment for this population. METHODS A total of 90 Chinese adult heart transplant recipients in the early stage were enrolled. CYP3A4*1G GA(rs2242480) genotype was assessed by pyrophosphate sequencing. CYP3A5*3 A>G(rs776746) and POR*28 C>T(rs1057868) genotype were determined by Sanger sequencing. Tacrolimus trough concentration(ρ0) was evaluated by enzyme multiplied immunoassay technique(EMIT). Associations between genotypes and ρ0/D as well as time and dose to get the target range were completely analyzed. RESULTS Allele frequencies of all the evaluated SNPs were consistent with Hardy-Weinberg equilibrium (P>0.05). The ρ0/D in CYP3A5*3/*3 carriers was considerably higher than that in *1/*1and *1/*3 carriers. Moreover, time to get the target range was significantly shortened and required dosage was also significantly reduced in CYP3A5*3/*3 carriers. The ρ0/D in CYP3A4*1/*1G carriers was remarkably decreased in comparison with the wild type. After stratification by CYP3A5*3 genotypes, no associations were observed between CYP3A4*1G and POR*28 genotypes and tacrolimus ρ0/D. POR*28 was not related to ρ0/D, but significantly prolonged time to target range. CONCLUSION This study demonstrats that CYP3A4*1G and CYP3A5*3 polymorphisms are associated with tacrolimus concentrations, the test of these genotypes before transplantation may be useful for individualized medicine of tacrolimus.

关键词

他克莫司 / CYP3A4/5 / POR / 心脏移植

Key words

tacrolimus / CYP3A4/5 / POR / heart transplant

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导出引用
周红, 张菁, 伍三兰, 刘亚妮, 师少军, 张玉, 韩勇. CYP3A4/5、POR基因多态性与中国成年心脏移植受者他克莫司血药浓度相关性的研究[J]. 中国药学杂志, 2017, 52(19): 1710-1714 https://doi.org/10.11669/cpj.2017.19.012
ZHOU Hong, ZHANG Jing, WU San-lan, LIU Ya-ni, SHI Shao-jun, ZHANG Yu, HAN Yong. Associations of CYP3A4/5 and POR Polymorphisms with Tacrolimus Concentrations in Chinese Adult Heart Transplant Recipients[J]. Chinese Pharmaceutical Journal, 2017, 52(19): 1710-1714 https://doi.org/10.11669/cpj.2017.19.012
中图分类号: R969.1   

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基金

华中科技大学自主创新研究基金重点专项资助(2015ZHYX014)
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