肾移植患者HGPRT活性及多态性与硫唑嘌呤所致不良反应的相关性研究

目的: 本研究旨在探索次黄嘌呤鸟嘌呤磷酸核糖转移酶(HGPRT)活性及基因多态性与硫唑嘌呤(AZA)所致不良反应的相关性,为临床合理使用AZA提供理论依据。方法: 用本实验室建立的HPLC法测定入选样本的HGPRT活性,直接测序法测定HGPRT IVS6-12C>A的基因型,结合受试者不良反应发生情况,分析HGPRT活性及多态性与AZA所致不良反应的相关性。结果: 86例肾移植受者HGPRT活性范围为(44.59~262.16)U,平均为(100.17±33.50)U,健康受试者HGPRT活性范围为(28.43~153.65) U,平均为(99.30±17.21)U,均呈正态分布。两组HGPRT活性均值差异无统计学意义(P>0.05)。304例肾移植患者中发现2例HGPRT IVS6-12C>A突变体,突变频率为 2.30%。而健康受试者中未发现突变,分析发现HGPRT活性与基因型之间无明显相关性(P>0.05)。流行性感冒样症状组患者的平均HGPRT活性明显高于肾移植对照组(147.47±101.24) U vs (100.46±29.31) U,P<0.05)],而血液毒性组、肝脏毒性组、胃肠道反应组与肾移植对照组比较,活性差异无统计学意义。AZA所致不良反应与HGPRT基因多态性之间没有明显相关性(P>0.05)。结论: 在服用AZA之前,测定患者HGPRT活性,筛选出HGPRT高活性者,减少AZA的初始剂量,有利于减少AZA所致流行性感冒样症状不良反应的发生率。

Association of HGPRT activity and gene polymorphism with adverse reactions caused by azathioprine in kidney transplant recipients

AIM: To explore the associations between HGPRT activities and genetic polymorphisms and AZA-related adverse reactions in renal transplant recipients so as to provide enough theoretic and experiment evidence for rational use of AZA.METHODS: Erythrocyte HGPRT activity were measured in 86 cases of renal transplant recipients by a modified high-performance liquid chromatography (HPLC) procedure we developed before,genotype of HGPRT IVS6-12C>A was determined by direct sequencing method.Combined with the subject occurrence of adverse reactions,the relationships between HGPRT activity and genetic polymorphisms and AZA-induced adverse reactions were systematically analyzed.RESULTS: HGPRT activity in 86 cases of renal transplant recipients ranged from 44.59 U to 262.16 U and the average activity was (100.17±33.50) U. HGPRT activity in healthy subjects ranged from 28.43 to 153.65 U and the average activity was (99.30±17.21)U. Both of them showed normal distribution.There was no statistically significant difference about HGPRT activity between the renal transplant recipients and the healthy subjects(P>0.05). In the renal transplant recipients, 2 cases of HGPRT-IVS6-12C> A mutation was found and the mutation frequency was 2.30%. No IVS6-12C> A mutation was found in the health subjects. No association was observed between HGPRT activity and genetic polymorphisms(P>0.05).The average HGPRT activity in patients with flu-like symptoms was significantly higher than that in the renal transplant recipients who had no AZA-related adverse reactions(147.47±101.24) U vs (100.46±29.31) U,P<0.05]. The average HGPRT activities in patients with hematotoxicity, hepatotoxicity and gastrointestinal disturbance were found no significant differences compared with the patients who had no AZA-related adverse reactions (P>0.05). No association was observed between HGPRT genetic polymorphisms and AZA-related adverse reactions(P>0.05).CONCLUSION: In conclusion, before commencing AZA treatment, it is important to measure HPGRT activity in renal transplant recipients and relieve AZA-dose in order to reduce AZA-related flu-like symptoms .