CYP3A5、ABCB1和POR基因多态性对肾移植受者他克莫司浓度、剂量及肾功能的长期影响

Long-term influences of CYP3A5,ABCB1 and POR polymorphism on dosage and concentration of tacrolimus and renal function in renal transplant patients

目的:研究CYP3A5、ABCB1和POR基因多态性对术后3个月以上肾移植受者他克莫司(FK506)剂量、浓度以及肾功能的影响。方法:选取某院行同种异体肾移植手术的320例患者为研究对象,采用聚合酶链式反应连接的限制性片段长度多态性(PCR-RFLP)分析法和测序法检测患者CYP3A5、ABCB1和POR基因型;由于CYP3A5*3基因突变导致CYP3A5酶失活,因此将CYP3A5*3*3定义为CYP3A5非表达者(n=163),将CYP3A5*1*1和CYP3A5*1*3定义为CYP3A5表达者(n=157),比较CYP3A5表达者和非表达者间FK506血药浓度、剂量、浓度剂量比及肾小球滤过率(eGFR)的差异。结果:在移植后1、4年,CYP3A5表达的FK506血药浓度低于非表达者(P=0.0067,P=0.0004),其剂量在移植后长达8年高于非表达者(P=0.0004),而浓度剂量比则低于非表达者(P=0.0060),差异均有统计学意义。ABCB13435、ABCB11236和POR基因多态性对FK506血药浓度、剂量及浓度剂量比均无影响,差异无统计学意义(P=0.3040,P=0.1190,P=0.3450)。在移植后3、6个月和2年后,CYP3A5非表达者的eGFR高于CYP3A5表达者,差异有统计学意义(P=0.0240,P=0.0187,P=0.0309),提示CYP3A5基因多态性对移植肾功能有长期影响。结论:CYP3A5基因多态性对肾移植受者FK506的浓度、剂量、浓度剂量比及移植后的肾功能有长期影响。

Objective:To investigate the effects of CYP3A5,ABCB1 and POR gene polymorphisms on dosage,blood concentration of tacrolimus and renal function in renal recipients over 3 months after transplantation.Methods:320 cases of renal transplant recipients were recruited as study objects.CYP3A5,ABCB1 and POR genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)and sequencing methods.The differences of tacrolimus blood concentration(C),dose(D),ratio of concentration to dose(C/D)and renal function(level of estimated glomerular filtration rate,eGFR)were compared among all of the genotypes groups over 3 months after transplantation.Results:The concentration of tacrolimus in CYP3A5 expresser group was significantly lower than those in CYP3A5 non-expresser group 1 year and 4 years after renal transplantation(P=0.0067,P=0.0004).8 years after the transplantation,D of the expresser group was higher than that of the non-expresser group(P=0.0004),while C/D was lower than that of the non-expresser group(P=0.006).ABCB13435,ABCB11236 and POR gene polymorphisms had no effects on tacrolimus C,D,and C/D,there being no statistical significance(P=0.3040,P=0.1190,P=0.3450).There were remarkable differences on the eGFR between CYP3A5 expresser group and non-expresser group 3 months,6 months and 2 years after transplantation(P=0.024,P=0.0187,P=0.0309),suggesting that gene polymorphisms had long term effect on renal function after transplantation.Conclusion:Polymorphism of CYP3A5 has long term impact on the C,D,C/D of tacrolimus,and renal function after transplantation.