小样本探讨黄嘌呤脱氢酶和鸟苷酸合成酶基因多态性对硫唑嘌呤所致骨髓抑制和脱发的影响

Effects of Xanthine Dehydrogenase and Guanosine Monophosphate Synthetase Gene Polymorphisms on Myelosuppression and Alopecia Induced by Azathioprine in Small Samples

关键词:  硫唑嘌呤  鸟苷酸合成酶  黄嘌呤脱氢酶  骨髓抑制  脱发

Key words:  azathioprine  guanosine monophosphate synthetase  xanthine dehydrogenase  myelosuppression  alopecia

摘要:

目的 研究黄嘌呤脱氢酶（xanthine dehydrogenase，XDH）和鸟苷酸合成酶（guanosine monophosphate synthetase，GMPS）基因多态性对硫唑嘌呤（azathioprine，AZA）所致骨髓抑制和脱发的影响，探讨上述位点联合NUDT15 rs116855232检测对预测AZA所致骨髓抑制的价值。方法 回顾性分析曾经服用或正在服用AZA治疗自身免疫性疾病患者，收集静脉血采用直接测序法测定GMPS rs61750368、rs61750369，XDH rs2295475、rs1884725、rs17011368、rs566362和NUDT15 rs116855232基因型。依据不良反应分为2组，分析上述基因型与AZA所致骨髓抑制和脱发的相关性，NUDT15 rs116855232作为对照位点。结果 共纳入80例患者，2组在年龄、日剂量、疗程、BMI以及6-硫鸟嘌呤核苷酸浓度均无显著性差异。Logistic回归分析表明，AZA所致骨髓抑制与XDH rs2295475突变相关（P=0.003，OR=3.10，95%CI：1.45~6.25），该基因预测骨髓抑制敏感度为69.6%，特异度为63.2%，ROC曲线AUC为0.66；NUDT15 rs116855232突变也和AZA所致骨髓抑制相关（P=0.008，OR=3.46，95%CI：1.21~9.93）；其余位点基因型暂未发现与骨髓抑制和脱发相关。rs116855232野生型且rs2295475突变型的患者对比两位点野生型的患者，其骨髓抑制的危险值升高（OR=6.53，P=0.004），而两位点同时突变者骨髓抑制的危险值更高（OR=51.67，P<0.001）。结论 在中国自身免疫性疾病患者中XDH rs2295475突变可能为AZA诱导骨髓抑制的独立危险因素，尽管预测准确度较低但仍有预测价值。尤其XDH联合NUDT15rs116855232监测，可能会弥补NUDT15野生型者对骨髓抑制预测不足的风险，提高NUDT15突变型对骨髓抑制预测的准确性，但以上结果还需更多临床研究验证。

Abstract:

OBJECTIVE To investigate the effects of xanthine dehydrogenase(XDH) and guanosine monophosphate synthetase(GMPS) gene polymorphisms on myelosuppression and alopecia induced by azathioprine(AZA). To explore the value that combined detection of NUDT15 rs116855232 and those genetypes predicted AZA induced myelosuppression. METHODS Patients who have taken or are taking AZA for autoimmune diseases were retrospective analysed. Genotypes of GMPS rs61750368, rs61750369, XDH rs2295475, rs1884725, rs17011368, rs566362 and NUDT15 rs116855232 were determined by direct sequencing. Patients were grouped according to adverse reactions. The association of these genotypes with AZA-induced myelosuppression and alopecia was analyzed, NUDT15 rs116855232 as control gene. RESULTS Eighty patients were included. There were no significant differences in age, daily dose, course of treatment, BMI and 6-thioguanine nucleotide level between two groups. Logistic regression analysis showed that AZA-included myelosuppression was associated with XDH rs2295475 mutation(P=0.003, OR=3.10, 95%CI:1.45-6.25). Sensitivity and specificity of this gene predicted myelosuppression were 69.6%, 63.2% respectively, ROC curve was 0.66. AZA-included myelosuppression was aslo associated with NUDT15 rs116855232 mutation(P=0.008, OR=3.46, 95%CI:1.21-9.93). No other genes were found to be associated with myelosuppression and alopecia. Patients with rs116855232 wild-type and rs2295475 mutant had higher risk of myelosuppression compared to those with two-gene wild-type(OR=6.53, P=0.004), while the patients with both genes mutated at the same time had much higher risk of myelosuppression(OR=51.67, P<0.001). CONCLUSION XDH rs2295475 mutation may be an independent risk factor for AZA-induced myelosuppression in Chinese autoimmune patients. Although the prediction accuracy is low but still has predictive value. Particularly, XDH combine with NUDT15 rs116855232 monitoring may compensate for the risk of inaccurate prediction of myelosuppression in NUDT15 wild-type patients. Combined testing can improve the accuracy of prediction of myelosuppression by NUDT15 mutant type. But these results are further validated by clinical studies.