CYP3A5和POR基因多态性对肾移植患者住院期间他克莫司浓度剂量的影响

目的：研究CYP3A5和POR基因多态性对肾移植患者住院期间他克莫司（FK506）浓度（C）、剂量（D）以及浓度剂量比（C/D）的影响。方法：以290例肾移植患者为研究对象，使用聚合酶链式反应（PCR）-限制性内切片段长度多态性（RFLP）法和测序法检测患者CYP3A5*3 A>G（rs776746）和POR*28 C>T（rs1057868）基因型，比较肾移植术后28 d内不同基因型患者之间FK506的C、D以及C/D的差异。结果：CYP3A5*3 GG型患者FK506的C和C/D在术后7、14、21、28 d均显著高于CYP3A5*3 AA型和AG型患者（P<0.01）。POR*28 CT型患者术后21 d和28 d的C/D与CC型患者相比具有显著性差异（P<0.05），而POR*28基因型对其他各时间点FK506的C、D以及C/D均无影响。根据CYP3A5*3基因分层后发现，POR*28基因多态性对CYP3A5*3 AA型患者FK506的C、D以及C/D影响最大，其次是CYP3A5*3 AG型，而对CYP3A5*3 GG型患者各时间点的C、D以及C/D均无影响。在CYP3A5*3 AA型患者中，术后各时间点POR*28 CC型FK506的D均低于CT和TT型患者，CC型患者的C/D均高于CT型和TT型，且在多个时间点处有统计学差异。结论：肾移植初期，CYP3A5*3和POR*28基因多态性对FK506的浓度剂量有影响，且POR*28基因多态性对CYP3A5*3 AA型患者FK506浓度剂量的影响最大。

Effect of CYP3A5 and POR polymorphism on dosage and concentration of tacrolimus in renal transplant patients during hospital stay

OBJECTIVE To investigate the effect of CYP3A5 and POR genetic polymorphism on the blood concentration(C), dose(D) and ratio of concentration to dose(C/D) of tacrolimus(FK506) in renal transplant recipients during hospitalization.METHODS 290 cases of renal transplant recipients were recruited. CYP3A5*3 A>G(rs776746) and POR*28 C>T(rs1057868) genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and sequencing methods. The differences of C, D and C/D of FK506 were compared among all of the genotype groups during 28 days after renal transplantation.RESULTS The C and C/D of FK506 in patients with CYP3A5*3 GG genotype were all significantly higher than those with CYP3A5*3 AA and AG genotype at 7, 14, 21 and 28 days after renal transplantation(P<0.01). There was a significant difference in C/D between patients with POR*28 CT and CC genotype at 21 and 28 days after renal transplantation(P<0.05), however, POR*28 genotype had no effect on C, D, and C/D of FK506 at other time points. Considering different CYP3A5*3 genotypes, it was found that the POR*28 gene polymorphism had exerted greatest effect on C, D and C/D of FK506 in patients with CYP3A5*3 AA genotype, followed by CYP3A5*3 AG genotype, then CYP3A5*3 GG genotype. POR*28 genotype had no effect on C, D and C/D of patients with CYP3A5*3 GG genotype. For patients with CYP3A5*3 AA genotype, the D in group with POR*28 CC genotype was lower than those with CT and TT genotypes at each time point after renal transplantation, and the C/D of CC genotype patients was higher than that of CT and TT genotype patients. There were statistical differences at multiple time points.CONCLUSION CYP3A5* 3 and POR* 28 gene polymorphisms have an effect on FK506 concentration and dosage in early stage of renal transplantation, and POR*28 gene polymorphism has the greatest effect on FK506 concentration and dosage in CYP3A5*3 AA patients.