CYP3A5、ABCB1基因多态性对中国肾移植患者服用他克莫司剂量和血药浓度的影响

目的：研究肾移植患者CYP3A5、ABCB1基因多态性对肾移植术后患者他克莫司（TAC）血药浓度及给药剂量的影响。方法：采集83例中国肾移植患者术后3个月内TAC的常规监测的谷浓度（C0）。测定受试者CYP3A5*3（rs776746）、ABCB1 1236C＞ T（rs1128503）、2677G＞ T/A（rs2032582）、3435C＞ T（rs1045642）位点的基因型，分析基因多态性对TAC的C0、剂量的影响。结果：患者CYP3A5、ABCB1基因型频率均符合Hardy-Weinberg平衡（P ＞ 0.05）。在移植后3个月期间，CYP3A5*3/*3型患者相较于携带*1等位基因患者，具有更高的C0和更低的剂量（P ＜ 0.05）。ABCB1 2677GG基因型的C0显著低于GT、GA、AA、TT、AT型（P ＜ 0.05）；3435CT型的C0显著高于CC、TT型（P ＜ 0.05）。根据ABCB1的单倍型进行分组，并与CYP3A5进行了联合分析，结果发现，发现CYP3A5*1/*1与*1/*3组与*3/*3组中，不同ABCB1单倍型对TAC血药浓度影响的差异无统计学意义。术后随时间延长，CYP3A5*3/*3型患者的TAC剂量逐步降低，而携带*1基因患者的剂量则呈增加趋势。结论：CYP3A5比ABCB1基因多态性对肾移植受者TAC血药浓度的影响更显著，若达到相同的血药浓度，CYP3A5*3/*3型患者每日所服用的剂量更低。根据CYP3A5基因型制定给药方案，有助于尽早达到浓度标准，达到精准治疗的目标。

Effects of CYP3A5 and ABCB1 Gene Polymorphisms on Dosages and Blood Concentrations of Tacrolimus in Chinese Kidney Transplant Patients

Objective: To investigate the effects of CYP3A5 and ABCB1 gene polymorphisms on blood concentrations and dosages of tacrolimus (TAC) in patients after kidney transplantation. Methods: TAC trough concentrations (C0) were collected for routine monitoring from 83 Chinese patients within 3 months after kidney transplant. Subjects were determined for their genotypes of CYP3A5*3(rs776746), ABCB1 1236C > T (rs1128503), 2677G > T/A (rs2032582), 3435C > T (rs1045642) loci, and of gene polymorphisms were analyzes for their effects on C0 and dose of TAC. Results: The frequencies of the tested CYP3A5 and ABCB1 genotypes were consistent with the Hardy Weinberg equilibrium (P > 0.05). During the three months after transplantation, patients with CYP3A5*3/*3 had higher C0 and lower dose (P < 0.05) compared with those carrying the *1 allele. The C0 of the ABCB1 2677GG genotype was significantly lower than thsoe of the GT, GA, AA, TT and AT genotypes (P < 0.05), and the C0 of the 3435CT genotype was significantly higher than those of the TT and CT genotypes (P < 0.05). In patients with CYP3A5*1/*1, *1/*3 and *3/*3 genotypes, there was no difference among various ABCB1 diplotypes. Over time after surgery, the TAC dose of the CYP3A5*3/*3 patients gradually decreased, while the dose of the patients carrying *1 allele showed an increasing trend. Conclusion: Compared with ABCB1, genetic polymorphism of CYP3A5 has a more significant impact on the C0 of TAC in Chinese kidney transplant recipients. To reach a similar C0, patients with a CYP3A5*3/*3 genotype need a lower daily TAC dose. Dosing regimen based on the CYP3A5 genotype may be helpful in achieving target TAC concentration early, and valuable in patients receiving immunosuppressive therapy after transplantation.