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

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

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）Uvs（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。

AIM： To explore the associations between HGPRT activities and genetic polymor- phisms and AZA-related adverse reactions in re- nal 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 trans- plant recipients by a modifiedzhigh-performance liquid chromatography （HPLC） procedure we developed before,genotype of HGPRT IVS6-12C 〉A was determined by direct sequencing meth- od. Combined with the subject occurrence of ad- verse reactions, the relationships between HG- PRT activity and genetic polymorphisms and AZA-induced adverse reactions were systemati- cally 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 andthe mutation frequency was 2.30%. No IVS6- 12C〉 A mutation was found in the health subjects. No association was observed between HG- PRT 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 gastrointesti- nal disturbance were found no significant differ- ences compared with the patients who had no AZA-related adverse reactions （P 〉 0.05）. No association was observed between HGPRT ge- netic polymorphisms and AZA-related adverse reactions（P〈0.05）. CONCLUSION- In conclu- sion, before commencing AZA treatment, it is important to measure HPGRT activity in renal transplant recipients and relieve AZA-dose in or- der to reduce AZA-related flu-like symptoms .