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 G>A(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*1G、CYP3A5*3、POR*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和*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*1G和CYP3A5*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 G>A(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
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Key words
tacrolimus /
CYP3A4/5 /
POR /
heart transplant
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中图分类号:
R969.1
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参考文献
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脚注
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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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