肾移植患者基因多态性对五酯胶囊增加他克莫司血药浓度的影响

Effects of Gene Polymorphism on the Increasing of Tacrolimus Blood Concentration Induced by Wuzhi Capsules in Renal Transplantation Patients

目的:探讨肾移植患者CYP3A4、CYP3A5等基因多态性对五酯胶囊增加他克莫司血药浓度的影响。方法:选取2015年8月-2018年11月于安徽医科大学第一附属医院进行肾脏移植手术并行门诊复查的汉族肾移植患者194例,根据其是否联合使用五酯胶囊分为单药组(107例)和联合组(87例)。单药组患者术后口服他克莫司胶囊0.1~0.15 mg/kg,bid+吗替麦考酚酯胶囊0.5~0.75 g,bid或麦考酚钠肠溶片360~540 mg,bid+醋酸泼尼松片10 mg,qd;联合组患者在单药组基础上加服五酯胶囊2粒,bid。两组患者均用药至少7 d。收集患者的性别、年龄等临床资料;采用酶放大免疫分析技术检测他克莫司稳态血药谷浓度,并计算血药谷浓度/日剂量(C/D)值;采用聚合酶链反应检测患者CYP3A5基因rs4646457、rs15524、rs776746,CYP3A4基因rs4646437、rs2242480、rs35599367,ABCB1基因rs1128503,ABCC2基因rs3740066,NR1I2基因rs3814055,POR基因rs1057868,PPARA基因rs4253728,IL-3基因rs181781,IL-10基因rs1800896,CTLA4基因rs4553808,CYP2C19基因rs4244285、rs4986893位点的分型。采用Kruskal-Wallis检验或Spearman秩相关检验分析各因素与他克莫司C/D值的相关性,并进行多元线性回归分析。结果:194例肾移植患者中,仅检出CYP3A4基因rs35599367、PPARA基因rs4253728野生型,其余各基因的分型分布均符合Hardy-Weinberg平衡(P>0.05)。单因素分析及多元线性回归分析结果显示,患者是否联用五酯胶囊以及CYP3A5基因rs776746位点多态性与他克莫司C/D值有关(P<0.05)。单药组和联合组CYP3A5基因不同分型患者C/D值组内比较,差异均有统计学意义(P<0.05),且单药组GG、AG型患者C/D值均显著低于联合组同基因型患者(P<0.05);两组AA型患者C/D值比较差异无统计学意义(P>0.05)。结论:联合使用五酯胶囊与否、CYP3A5基因rs776746位点多态性与汉族肾移植患者体内他克莫司的血药浓度有关;联用五酯胶囊能提高该基因GG、AG型患者体内他克莫司的血药浓度,而对AA型患者的影响并不明显。

OBJECTIVE:To investigate the effects of polymorphism of CYP3A4,CYP3A5 and other genes on the increasing of tacrolimus blood concentration by Wuzhi capsules in renal transplantation patients.METHODS:Totally 194 patients in Han nationality underwent renal transplantation and received outpatient follow-up after surgery were selected from the First Affiliated Hospital of Anhui Medical University during Aug.2015-Nov.2018,and then divided into single drug group(107 cases)and combination group(87 cases)according to using of Wuzhi capsules or not.Single drug group was given Tacrolimus capsules 0.1-0.15 mg/kg,po,bid+Mycophenolate mofetil capsules 0.5-0.75 g,bid or Mycophenolate sodium enteric-coated tablets 360-540 mg,bid+Prednisone acetate tablets 10 mg,qd;combination group was additionally given two Wuzhi capsules,bid,on the basis of single drug group.Two groups were treated at least 7 d.The clinical data(such as patients’sex and age)were collected,and enzyme amplification immunoassay was used to detect steady-state valley concentration of tacrolimus,and calculate valley concentration/daily dose(C/D)value.PCR was adopted to detect patient genotyping of CYP3A5 gene rs4646457,rs15524 and rs776746 locus,CYP3A4 gene rs4646437,rs2242480 and rs35599367 locus,ABCB1 gene rs1128503 locus,ABCC2 gene rs3740066 locus,NR1I2 gene rs3814055 locus,POR gene rs1057868 locus,PPARA gene rs4253728 locus,IL-3 gene rs181781 locus,IL-10 gene rs1800896 locus,CTLA4 gene rs4553808 locus,CYP2C19 gene rs4244285 and rs4986893 locus,respectively.The correlation of each factor and tacrolimus C/D value was analyzed by Kruskal-Wallis test or Spearman rank test.Multivariate linear regression was conducted.RESULTS:In 194 renal transplanation patients,only wild type at rs3599367 locus of CYP3A4 gene and rs4253728 locus of PPARA gene were detected,and each genotype distribution of other genes was consistent with the Hardy-Weinberg equilibrium(P>0.05).Single factor analysis and multiple linear regression analysis showed that the combination of Wuzhi capsules and rs776746 polymorphism of CYP3A5 gene were related to tacrolimus C/D value(P<0.05).There was statistical significance in tacrolimus C/D values among different genotypes of CYP3A5 gene in single drug group and combnation group(P<0.05).C/D value of GG and AG genotype in single drug group were significantly lower than combination group(P<0.05),while there was no statistical significance in tacrolimus C/D value of AA genotype between 2 groups(P>0.05).CONCLUSIONS:Combination of Wuzhi capsules or not and polymorphism of CYP3A5 gene rs776746 locus are associated with blood concentration of tacrolimus in renal transplantation patients in Han nationality.Combined use of Wuzhi capsules can increase blood concentration of tacrolimus in GG and AG genotype,but have no significant effect on AA genotype.