联合检测供体细胞色素P4503A亚家族多肽5和受体细胞色素P4503A亚家族多肽4基因多态性对肝移植术后他克莫司个体化用药的影响

Combined effect of donor cytochrome P450 3A family polypeptide 5 and recipient cytochrome P450 3A family polypeptide 4 polymorphisms on the individual dosage regimen of tacrolimus in Chinese liver transplant patients

目的探讨肝移植供体细胞色素P4503A亚家族多肽5（CYP3A5）rs776746与受体细胞色素P4503A亚家族多肽4（CYP3A4）rs12333983位点单核苷酸多态性与他克莫司血药浓度／给药剂量的关系。方法观察90例接受肝移植的受体在术后1个月内每周的全血谷浓度和给药剂量，并应用测序技术检测所有受体和相应供体CYP3A5 rs776746和CYP3A4 rs12333983位点的单核苷酸多态性，分析不同基因型与他克莫司代谢表型[全血谷浓度／给药剂量比值（C／D）值]的相关性。结果肝移植术后1个月内，供体CYP3A5 rs776746及受体CYP3A4 rs12333983位点基因多态性与患者他克莫司C／D值明显相关，不存在连锁不平衡关系（D’=0．017，r^2〈0．001）。将两位点行联合分析后发现，术后1个月内每周的C／D值呈“快代谢组（n=22）〈中间代谢组（n=44）〈慢代谢组（n=24）”，差异有统计学意义（P〈0．05）。结论联合检测供体CYP3A5 rs776746和受体CYP3A4 rs12333983位点基因型有助于指导他克莫司个体化用药。

Objective To investigate the effect of donor cytochrome P450 3A family polypeptide 5 （ CYP3A5 ） and recipient cytochrome P450 3A family polypeptide 4 （CYP3A4） gene polymorphisms on the concentration/dose （C/D） ratio of tacrolimus in Chinese liver transplant patients. Methods Ninety liver transplant recipients treated with tacrolimus and their co-respective donors were enrolled in this study. Tacrolimus dosage and trough blood concentration were determined at 1st month after liver transplantation. Polymerase chain reaction （PCR） amplification and DNA sequencing were applied to detect CYP3A5 rs776746 and CYP3A4 rs12333983 polymorphisms for all subjects. The relationship between gene polymorphisms and tacrolimus C/D ratios was analyzed. Results Both donor CYP3A5 rs776746 and recipient CYP3A4 rs12333983 polymorphisms were highly correlated with the tacrolimus C/D ratios at first month af- ter liver transplantation. No linkage disequilibrium between donor CYP3A5 rs776746 and recipient CYP3A4 rs12333983 polymorphisms was observed （D＇ = 0. 017, r^2 〈 0. 001 ）. The combined effect of these two polymorphisms demonstrated that there was significant difference in tacrolimus C/D ratio among groups. The trend of tacrolimus C/D ratios was highly significant at all investigated time points： extensive metabolizers （ n = 22） 〈 intermediate metabolizers （ n = 44） 〈 poor metabolizers （ n = 24）. Conclusion Combined detection of donor CYP3 A5 and recipient CYP3A4 genotypes may be performed prospectively to help individualize tacrolimus dose regimen for liver transplant patients.