CYP3A4、CYP3A5和CYP2D6基因单核苷酸多态性对肾移植术后稳定期患者他克莫司代谢的影响

The influence of CYP3A4,CYP3A5 and CYP2D6 single nucleotide polymorphism on tacrolimus metabolism in renal transplantation patients during stable period

目的探讨肾移植患者细胞色素P450 CYP3A4、CYP3A5和CYP2D6基因单核苷酸多态性与他克莫司(FK506)代谢的相关性以及根据基因多态性制定FK506个体化治疗方案的可行性。方法收集随访的138例肾移植稳定期患者,均采用含FK506、吗替麦考酚酯、糖皮质激素的三联治疗方案。记录单位体重用药剂量数据、FK506谷浓度和CYP3A4、CYP3A5、CYP2D6基因单核苷酸多态性测序法检测结果。分析单核苷酸多态性与浓度调整的单位体重用药剂量的相关性。结果在138例患者中,CYP3A4野生型TT等位基因频率为0.993、杂合子TC等位基因频率为0.007;CYP3A5野生型AA等位基因频率为0.529、杂合子AG等位基因频率为0.399、纯合子GG等位基因频率为0.072;CYP2D6野生型(76例)CC等位基因频率为0.550、杂合子CT等位基因频率为0.449。为了达到相应的稳态浓度,CYP3A5野生型(AA)患者与突变型(AG、GG)相比需要更高剂量的FK506(P<0.001);而CYP2D6野生型(CC)和突变型(CT)之间FK506剂量差异无统计学意义(P>0.05)。结论CYP3A4的基因多态性以野生型常见,对FK506代谢的影响较少。CYP3A5的基因多态性与FK506的代谢密切相关,野生型患者需要较高剂量的FK506才能达到相应的稳态浓度。CYP2D6的基因多态性与FK506代谢无明显相关性。

Objective To investigate the influence of cytochrome P450 CYP3A4, CYP3A5 and CYP2D6 single nucleotide polymorphism on tacrolimus （ FKS06 ） metabolism, and to study the feasibility of personalized base treatment of FKS06. Methods A total of 138 renal transplantation patients during stable period were followed up. All patients received FKS06, mycophenolate mofetil and prednisolone treatment. Drug dose per body weight was recorded, the trough concentration of FKS06 was calculated, and gene sequencing was used to detect single nucleotide polymorpbism of CYP3A4, CYP3A4 and CYP2D6. The drug dose per body weight of FKS06 and its relationship with single nucleotide polymorphism were analyzed. Results Among the 138 patients genotyped for CYP3A4, 138 patients displayed wild type TY （ allele frequency 0. 993 ）, heterozygous TC （0. 007 ）. There were CYP3A5 wild type AA （ 0. 529 ）, heterozygous AG （0. 399） and homozygous GG （0.072）. CYP2D6 showed 76 ease of wild type CC （0. 550） and heterozygous CT （0. 449 ）. Compared to heterozygous and homozygous alleles, CYP3A5 wild type （AA） and mutant type （AG and GG） expressed higher FKS06 dose （P 〈 0. 001 ）. CYP2D6 wild type （CC） and mutant type （CT） had no statistical significance with FKS06 dose （ P 〉 0. 05 ） . Conclusions The CYP3A4 genotype polymorphism is mainly wild type, and the significance for FKS06 metabolism is minimal. CYP3A5 has a major role in FKS06 metabolism, and the patients with wild type need high dose of FKS06. The CYP2D6 polymorphism has no correlation with FKS06 metabolism.