CYP3A5、UGT1A1、UGT2B7基因多态性与肾移植受者他克莫司血药浓度的相关性研究

Research on the Association of CYP3A5, UGT1A1 and UGT2B7 Gene Polymorphisms and the Plasma Concentrations of Tacrolimus from Kidney Recipients

目的:探讨CYP3A5、UGT1A1、UGT2B7基因多态性与肾移植受者他克莫司血药浓度的相关性。方法:共纳入124例肾移植术后采用他克莫司+霉酚酸酯+泼尼松三联治疗方案的患者。采用酶放大免疫测定法(Emit)检测他克莫司血药浓度;采用实时荧光定量PCR方法和Taqman基因分型技术测定CYP3A5*3、UGT1A1*6、UGT2B7*3、UGT1A1*28、UGT2B7*2基因多态性;应用Kruskal-Wallis H检验法分析5个SNPs基因多态性与他克莫司血药浓度的相关性。结果:CYP3A5*3突变型的他克莫司血药浓度GG/AG(7.75±2.56)/(6.75±1.85)ng·mL^(-1)显著高于野生型AA(5.00±1.81)ng·mL^(-1)(P<0.01);UGT1A1*6基因型GG/AG的血药浓度分别为(7.15±2.72)/(6.74±1.81)ng·mL^(-1),显著高于基因型AA(4.45±0.49)ng·mL^(-1)(P=0.022)。UGT2B7*3基因型GG/GT的血药浓度分别为(7.00±1.95)、(7.48±2.22)ng·mL^(-1),显著高于基因型TT(6.78±3.00)ng·mL^(-1)(P=0.014)。UGT1A1*28与UGT2B7*2基因多态性与他克莫司血药浓度无显著相关性(P>0.05)。结论:他克莫司血药浓度与CYP3A5*3、UGT1A1*6、UGT2B7*3基因多态性相关。

Objective:To investigate the association of CYP3A5,UGT1A1 and UGT2B7 gene polymorphisms and the plasma concentrations of tacrolimus.Methods:A total of 124 renal transplantation recipients who received tacrolimus-prednisone-mycophenolate mofetil were enrolled.The plasma concentrations of tacrolimus were measured by an enzyme-multiplied immunoassay technique(EMIT).At the same time,the real-time PCR and Taqman SNP genotyping methods were used to detect the polymorphisms of CYP3A5*3,UGT1A1*6,UGT1A1*28,UGT2B7*2,UGT2B7*3.The Kruskal-Wallis H test was used to analyze the effects of the 5 single nucleotide polymorphisms on the plasma concentrations of tacrolimus.Results:The plasma concentrations of tacrolimus with a CYP3A5*3 mutant like GG/AG(7.75±2.56)/(6.75±1.85)ng·mL^(-1)were obviously higher than those of the wild-type AA(5.00±1.81)ng·mL^(-1)(P<0.01).The plasma concentrations of tacrolimus with UGT1A1*6 genotypes GG/AG(7.15±2.72)/(6.74±1.81)ng·mL^(-1)were significantly higher than those of the genetype AA(4.45±0.49)ng·mL^(-1)(P=0.022).The plasma concentrations of tacrolimus with UGT2B7*3 genotypes GG/GT were(7.00±1.95)/(7.48±2.22)ng·mL^(-1),which were also significantly higher than those of the genotype TT(6.78±3.00)ng·mL^(-1)(P=0.014).There were no significant association between the UGT1A1*28 or UGT2B7*2 gene polymorphisms and their plasma concentrations of tacrolimus(P>0.05).Conclusion:The plasma concentrations of tacrolimus were associated with the CYP3A5*3,UGT1A1*6 and UGT2B7*3 genetic polymorphisms.