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目的:探究肾移植受者ABCC2-24C/T基因多态性是否与吗替麦考酚酯(MMF)所致相关不良反应有关。方法:将236例肾移植患者按不良反应类型分为骨髓抑制组、胃肠道反应组、感染组和未发生不良反应的对照组,采用高效液相-荧光检测器法测定患者的霉酚酸(MPA)血浆药物浓度,采用限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)法检测患者ABCC2-24C/T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,将患者基因型与患者的年龄、性别、体质量、体质指数(BMI)、透析时间、是否尸肾以及移植术后3,6,12,24,36个月时的MMF剂量、浓度进行统计学分析。结果:本研究中共有36例骨髓抑制,15例胃肠道反应,26例感染,124例为未发生不良反应,ABCC2-24C/T基因突变频率为21.34%,野生纯合子为58.05%,杂合子为37.71%,突变纯合子为4.24%,骨髓毒性组CC基因型分布显著高于对照组(P<0.05),CT基因型组与CC基因型组在年龄上存在显著差异(P<0.05),各不良反应组与对照组在BMI值和用药时间上差异均有统计学意义(P<0.05),骨髓毒性组在透析时间上与对照组差异均有统计学意义(P<0.05)。不同时间点各基因型MMF谷浓度的差异无统计学意义(P>0.05)。Logistic回归模型显示,ABCC2-24CC基因型、用药时间、术后3月的MMF谷浓度是肾移植术后发生MMF所致骨髓抑制毒性的危险因素。结论:ABCC2-24C/T位点的多态性与肾移植术后MMF所致相关不良反应有关,携带ABCC2-24CC基因型的患者更容易发生MMF所致骨髓抑制毒性。
OBJECTIVE: To investigate whether ABCC2-24C / T polymorphism in kidney transplant recipients is associated with adverse effects associated with mycophenolate mofetil (MMF). Methods: 236 patients with renal allograft were divided into two groups according to their adverse reactions: bone marrow suppression group, gastrointestinal reaction group, infection group and control group without adverse reaction. The mycophenolic acid (MPA) plasma concentrations were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to detect ABCC2-24C / T polymorphism in patients with the PCR products were sent to the sequencing company Direct sequencing to verify the accuracy of the results, the patient’s genotype and the patient’s age, gender, body mass, body mass index (BMI), dialysis time, whether the dead corpse and 3,6,12,24,36 months after transplantation When the MMF dose and concentration for statistical analysis. Results: There were 36 cases of myelosuppression, 15 cases of gastrointestinal reaction and 26 cases of infection. There were no adverse reactions in 124 cases. The frequency of ABCC2-24C / T mutation was 21.34% and that of wild homozygotes was 58.05% (P <0.05). The distribution of CC genotype in bone marrow toxicity group was significantly higher than that in control group (P <0.05). There was significant difference in age between CT genotype group and CC genotype group (P <0.05) There was significant difference in BMI value and medication time between each adverse reaction group and the control group (P <0.05). There was significant difference between the bone marrow toxicity group and the control group in the bone marrow toxicity group (P <0.05). There was no significant difference in the concentration of MMF trough at different time points (P> 0.05). Logistic regression model showed that ABCC2-24CC genotype, medication duration, and MMF trough concentration at 3 months after surgery were the risk factors of myelosuppression induced by MMF after renal transplantation. CONCLUSION: Polymorphism of ABCC2-24C / T locus is associated with adverse effects of MMF after renal transplantation. Patients with ABCC2-24CC genotype are more likely to develop myelosuppression induced by MMF.