UGT1A8*2基因多态性与肝移植患者术后吗替麦考酚酯所致不良反应的相关性研究

目的：探究肝移植受者UGT1A8^*2（G173C227）基因多态性是否与霉酚酸酯（mycophenolate mofetil，MMF）所致相关不良反应有关。方法：将105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；记录患者的年龄、性别、身高、质量、BMI值、移植年月等临床资料以及患者移植术后3，6，12，24月时的MMF口服日剂量、浓度、血糖、血常规、血脂及肝功能，并对以上数据进行统计学分析；采用酶增强免疫测定技术（EMIT^©2000）测定肝移植受者霉酚酸（mycophenolic acid，MPA）血药浓度；采用限制性片段长度多态性（PCR-RFLP）法检测105例患者UGT1A8^*2（G173C227）位点的多态性。结果：105例入组患者中，16例骨髓抑制，7例胃肠道反应，11例感染；UGT1A8^*2（G173C227）基因突变频率为58.57%，骨髓毒性组GG基因型的分布明显高于对照组（P<0.05）；术后3月时GG基因型组的谷浓度显著高于CC基因型组（P<0.05）；Logistic回归模型显示，UGT1A8^*2（G173C227）GG基因型是肝移植术后发生MMF所致骨髓抑制毒性的危险因素。结论：UGT1A8^*2（G173C227）位点的多态性与肝移植术后MMF所致相关不良反应有关，GG基因型患者更容易发生骨髓抑制毒性。

Association of UGT1A8*2 polymorphisms with adverse reactions caused by mycophenolate mofetil (MMF) in liver transplant recipients

OBJECTIVE To investigate the association between genetic polymorphisms of UGT1A8^*2(G173C227) and the adverse reactions of mycophenolate mofetil in liver transplant patients.METHODS 105 cases of liver transplant patients were divided into myelosuppression group,gastrointestinal reaction group and infection control group according to the type of adverse reactions.The clinical data such as age,gender,height,mass,BMI value,year and month of transplantation,MMF oral daily dose,concentration,blood glucose,blood routine,blood lipid and liver function at 3,6,12 and 24 months after transplantation were recorded,and the above data were statistically analyzed.Enzyme-enhanced immunoassay (EMIT 2000) was used to determine the plasma concentration of mycophenolic acid (MPA) in liver transplant recipients;restriction fragment length polymorphism (PCR-RFLP) was used to detect the polymorphism of UGT1A8^*2 (G173C227) locus in 105 patients.RESULTS Of the 105 enrolled patients,16 had myelosuppression,7 had gastrointestinal reactions,and 11 had infection;the frequency of UGT1A8^*2 (G173C227) gene mutation was 58.57%,and the distribution of GG genotype in the myelotoxicity group was significantly higher than that in the control group (P<0.05);the trough concentration in the GG genotype group was significantly higher than that in the CC genotype group at 3 months after surgery (P<0.05);logistic regression model showed that the UGT1A8^*2 (G173C227) GG genotype was a risk factor for MMF-induced myelosuppressive toxicity after liver transplantation.CONCLUSION The polymorphism of UGT1A8^*2 (G173C227) locus is related to the adverse reactions induced by MMF after liver transplantation.Patients with GG genotype are more likely to develop bone marrow suppression toxicity.