CYP3A5基因多态性对儿童肝移植患者他克莫司血药浓度的影响

Effect of CYP3A5 gene polymorphisms on tacrolimus concentration in pediatric liver transplant patients

目的研究供体和受体细胞色素P450（CYP）3A5酶6986位点的基因多态性对儿童肝移植患者他克莫司（FK506）浓度/剂量比（C0/D）的影响。方法收集2013年1月到2015年10月共127例儿童肝移植患者供受体外周血标本，进行CYP3A5基因分型的检测，收集患儿术后2个月内每周及术后第3个月他克莫司剂量、血药浓度。根据基因型将CYP3A5＊1/＊1及CYP3A5＊1/＊3为CYP3A5表达型，属于快代谢组，CYP3A5＊3/＊3为CYP3A5非表达型，属于慢代谢组，比较供、受体不同基因型间他克莫司的浓度/剂量（C0/D）比的差异。结果受体快代谢组比受体慢组术后2个月内每周及术后第3个月浓度/剂量比显著降低，差异有统计学意义（P〈0.05）；供体快代谢组比供体慢代谢组术后3周至2个月及第3个月浓度/剂量比显著降低，差异有统计学意义（均P〈0.05）；供/受体表达组、供体表达/受体无表达组和受体表达/供体无表达组三组的浓度/剂量比之间差异虽无统计学意义（P〉0.05），但供体非表达/受体非表达组和上述三组比较，浓度/剂量比显著增加，差异均有统计学意义（均P〈0.05）。结论供、受体两方的CYP3A5基因多态性都会影响儿童肝移植患者他克莫司的血药浓度，但受体自身的CYP3A5基因型对他克莫司影响更显著，供体/受体中只要其中一方含有CYP3A5＊1等位基因，达到同样的血药浓度所需的他克莫司剂量就会比供、受体都是慢代谢型的患儿相应增加。可以根据CYP3A5基因多态性调整剂量，进行个体化给药。

ObjectiveTo evaluate the effect of cytochrome P450（CYP）3A5 genes of both donors and recipients on the concentration/dosage ratio（C/D） of tacrolimus in pediatric liver transplant patients.MethodsA total of 127 pediatric liver transplant patients received tacrolimus. CYP3A5 polymorphism of donors and recipients were measured at the time of transplantation and then tacrolimus-based immunosuppressive therapy was started on the basis of individual genetic constitution. CYP3A5＊1/＊1 genotype and ＊1/＊3 genotype were combined into expressor genotype and ＊3/＊3 genotype non-expressor group. The C/D of tacrolimus during 3 months after surgery was analyzed in relation to CYP3A5 genotype.ResultsC/D of tacrolimus in patients with CYP3A5＊1 expressed donor was lower than C/D of patients with CYP3A5＊1 unexpressed donor （P〈0.05）; C/D in CYP3A5＊1-carried patients was also lower than CYP3A5＊1 non-expressors （all P〈0.05）. C/D in CYP3A5＊3/＊3 patients with CYP3A5＊3/＊3 donor was obviously higher than 3 other groups during 3 months after transplantation （all P〈0.05） and the difference of C/D was not statistically significant among 3 other groups （all P〉0.05）.ConclusionsCYP3A5＊1 genotype in donors as well as in patients both contributes to inter-individual variation in C/D of tacrolimus during adult liver transplantation. The recipients with CYP3A5＊ 1 allelic genes need a higher optimal dose of tacrolimus. Patients can benefit from setting and adjusting FK506 doses according to CYP3A5 genotype of both donors and recipients.