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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。CYP3 A5~*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CYP3 A5分层分析,在CYP3 A5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。
Objective To investigate the correlation between the CYP3A4 / 5 and POR SNPs and the dose-corrected concentration (ρ0 / D) of tacrolimus in Chinese adult cardiac transplant recipients and to provide a personalized dose adjustment program for this population reference. Methods A total of 90 recipients of Chinese adult cardiac transplantations were enrolled in this study. CYP3A4 ~ * 1G G> A (rs2242480) was detected by pyrosequencing and Sanger method was used to detect CYP3A5 ~ * 3 A> G (rs776746), POR * 28 C> T (rs1057868), Enzyme-amplified immunoassay (EMIT) was used to determine tacrolimus concentration. The genotypes were analyzed for correlation with ρ0 / D, time to target concentration, and dose required to reach target concentration. Results The frequencies of CYP3A4 ~ * 1G, CYP3A5 ~ * 3, POR ~ * 28 alleles were in line with the Hardy-Weinberg genetic balance. CYP3 A5 ~ * 3 / ~ * 3 genotype heart transplantation patients ρ0 / D ratio ~ * 1 / ~ * 1 and ~ * 1 / ~ * 3 carriers increased significantly reaching the target concentration time was significantly shorter, reaching the desired target concentration The dose was significantly reduced. The ρ0 / D of CYP3A4 ~ * 1 / ~ * 1G allele was significantly lower than that of wild type. Based on the CYP3 A5 stratification analysis, CYP3A4 and POR genotypes had no correlation with ρ0 / D of tacrolimus in CYP3 A5 expression and non-expression groups. POR ~ * 28 / ~ * 28 genotype recipients reached a target concentration significantly longer time. Conclusion The genotypes of CYP3A4 ~ * 1G and CYP3A5 ~ * 3 in Chinese adult cardiac transplant recipients are significantly correlated with ρ0 / D of tacrolimus. The detection before transplantation will contribute to the clinical individualized use of tacrolimus.