ABCG2 421C>A基因多态性与肾移植患者术后吗替麦考酚酯所致不良反应的相关性研究

Association of ABCG2 421C > A Polymorphism with Adverse Reactions of Mycophenolate Mofetil in Kidney Transplant Recipients

目的:研究肾移植术后患者ABCG2 421C>A基因多态性对吗替麦考酚酯(MMF)所致不良反应的影响。方法:对236例患者按不良反应类型分为骨髓抑制组、胃肠道反应组、感染组和对照组,并对患者的肾源、年龄、性别、身高、体质量、体质指数(BMI)、透析时间、移植年月等临床资料以及患者移植术后3,6,12,24,36个月时的MMF剂量进行统计学分析;采用高效液相-荧光检测器法测定肾移植受者的MMF血药浓度;采用限制性片段长度多态性(PCR-RFLP)法检测236例患者的ABCG2 421C>A位点多态性,并将PCR产物送测序公司直接测序以验证结果的准确性。结果:有36例骨髓抑制,15例胃肠道反应,26例感染,124例未发生不良反应,ABCG2 421C>A基因突变频率为34.32%,野生纯合子(CC)构成比为43.64%,突变杂合子(CA)为44.07%,突变纯合子(AA)为12.29%,胃肠道反应组AA基因型分布明显高于对照组(26.67%vs.9.43%,P=0.041),ABCG2 421 AA基因型组与CC、CA基因型组在性别上分布的差异有统计学意义(PCC=0.002、PCA=0.036);Logistic回归分析显示,ABCG2 421AA基因型是肾移植术后发生MMF所致胃肠道反应的独立危险因素。结论:肾移植术后患者ABCG2 421C>A基因多态性与MMF所致不良反应有关,ABCG2 421AA基因型患者更容易发生MMF所致胃肠道反应。

Objective： To investigate the association between ABCG2 421C 〉 A gene polymorphism and the adverse reactions of mycophenolate mofetil （MMF） in kidney transplant patients. Methods： Totally 236 cases of kidney transplant patients were divided into bone marrow suppression group, gastrointestinal tract reaction group, infection group and the control group according to the adverse reaction type. The genotype, age, gender, body weight, BMI, dialysis duration, cadaveric kidney or living relative kidney and the oral daily dose and concentration of MMF in 3, 6, 12, 24 and 36 months of the patients were statistically analyzed using SPSS 20.0 soft- ware. The plasma concentration of MMF was determined by an HPLC-fluorescence detector. The polymorphisms of ABCG2 421C 〉 A were detected by PCR-RFLP, and the PCR products were directly sent to a sequencing company to verify the accuracy of the results. Results ： Among the 236 patients, there were 36 cases of myelosuppression, 15 cases of gastrointestinal reactions, 26 cases of infection and 124 cases without adverse reaction. The mutation frequency of ABCG2 421C 〉 A gene was 34.32%, wild homozygote was 43.64%, heterozygote was 44.07%, and the homozygous was 12.29%. The frequency of AA genotype in gastrointestinal reaction group was significandy higher than that in the control group （26.67% vs. 9.43% , P = 0. 041 ）. The genotype frequency of ABCG2 421C 〉 A with AA genotype was significantly different from that with CC and CA genotype （Pcc = 0. 002, PcA = 0. 036）. Logistic re- gression analysis showed that ABCG2 421AA genotype was an independent risk factor for MMF-induced gastrointestinal reactions after renal transplantation. Condusion： ABCG2 421C 〉 A gene polymorphism is associated with adverse reactions caused by MMF after re- nal transplantation, and the individuals carrying ABCG2 421AA are prone to suffer from MMF-induced gastrointestinal reactions.