UGTs、ABCC2、SLCO1B1和IMPDH基因多态性与肾移植患者霉酚酸酯代谢和不良反应的相关性研究

Association of UGTs,ABCC2,SLCO1B1 and IMPDH Gene Polymorphisms with the Metabolism and Adverse Reactions of Mycophenolate Ester in Renal Transplant Patients

目的探讨UGTs、ABCC2、SLCO1B1和IMPDH基因多态性与肾移植术后早期受者霉酚酸酯代谢和不良反应的相关性。方法共纳入233例活体肾移植术后采用他克莫司+糖皮质激素+霉酚酸酯三联治疗方案的患者,采用基质辅助激光解吸电离飞行时间质谱方法检测13个基因位点的单核苷酸多态性,用Kruskal-Wallis H检验分析13个单核苷酸多态性对肾移植术后早期受者霉酚酸的体内暴露量/剂量(AUC/D)及不良反应的影响。结果UGT2B7802C>T CC和CT基因型受者霉酚酸的AUC/D分别为(36.03±16.19)和(38.06±15.41)mg·h·L^-1/g·d^-1,显著低于TT基因型受者的(43.63±15.10)mg·h·L^-1/g·d^-1(P=0.021)。SLCO1B1521T>C TT、TC和CC基因型受者MPA的AUC/D分别为(36.78±15.70)、(41.27±12.92)和(45.10±21.32)mg·h·L^-1/g·d^-1,组间有显著性差异(P=0.036)。13个单核苷酸多态性与不良反应间差异无统计学意义(P>0.05)。结论肾移植术后早期受者霉酚酸的AUC/D与UGT2B7802C>T和SLCO1B1521T>C基因多态性相关。

OBJECTIVE To investigate the association of UGTs,ABCC2,SLCO1B1 and IMPDH gene polymorphisms with metabolism and adverse reaction of mycophenolate ester in early renal transplant recipients.METHODS A total of 233 patients who received tacrolimus+glucocorticoid+mycophenolate mofetil treatment after living kidney transplantation were enrolled.Single nucleotide polymorphisms of 13 gene were detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.Kruskal-Wallis H test was used to analyze the effect of 13 single nucleotide polymorphisms on the exposure/dose(AUC/D)and adverse reactions of mycophenolic acid in early recipients after renal transplantation.RESULTS The AUC/D of mycophenolic acid in UGT2B7802C>T CC and CT genotype recipients was(36.03±16.19)and(38.06±15.41)mg·h·L^-1/g·d^-1,which was significantly lower than that in TT genotype recipients(43.63±15.10)mg·h·L^-1/g·d^-1(P=0.021).The AUC/D of mycophenolic acid in SLCO1B1521T>C TT,TC and CC genotype recipients were(36.78±15.70),(41.27±12.92)and(45.10±21.32)mg·h·L^-1/g·d^-1,respectively.There was significant difference between groups(P=0.036).There was no significant difference between 13 single nucleotide polymorphisms and adverse reactions(P>0.05).CONCLUSION The AUC/D of mycophenolic acid in early recipients after kidney transplantation are associated with the polymorphism of UGT2B7802C>T and SLCO1B1521T>C.