中国药物警戒 ›› 2020, Vol. 17 ›› Issue (10): 665-671.
DOI: 10.19803/j.1672-8629.2020.10.04

• 基础与临床研究 • 上一篇    下一篇

硫唑嘌呤致AOX1和MOCOS基因型药品不良反应相关性分析

钱家健1, 陈超1, 王振疆1, 黄载伟1, 张晓敏2, 艾新波1,*   

  1. 1珠海市人民医院（暨南大学附属珠海医院）,广东 珠海 519000;
    2遵义医科大学第五附属（珠海）医院,广东 珠海 519000
  • 收稿日期:2020-10-14 修回日期:2020-10-14 出版日期:2020-10-15 发布日期:2020-10-13
  • 通讯作者: *艾新波,男,在读博士,主治医师,消化内科。E-mail：sunhua@imm.ac.cn
  • 作者简介:钱家健,男,硕士,主管药师,临床药学。
  • 基金资助:
    广东省医学科学技术研究基金项目（A2017617）：IBD患者XO和GMPS活性及基因多态性与硫唑嘌呤不良反应的相关性研究; 广东省医院药学研究基金（2017A21）：硫唑嘌呤联合肠内营养维持克罗恩病临床缓解的疗效与安全

Analysis of the Association of AOX1 and MOCOS Polymorphisms with Azathioprine-induced Adverse Drug Reaction

QIAN Jiajian1, CHEN Chao1, WANG Zhenjiang1, HUANG Zaiwei1, ZHANG Xiaomin2, AI Xinbo*   

  1. 1Zhuhai People's Hospital(Zhuhai Hospital Affiliated with Jinan University), Zhuhai Guangdong 51900, China;
    2the Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai Guangdong 51900, China
  • Received:2020-10-14 Revised:2020-10-14 Online:2020-10-15 Published:2020-10-13

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摘要： 目的 以核苷二磷酸连接部分X型基序15（NUDT15）rs116855232作为对照位点,分析醛氧化酶1（AOX1）rs55754655和钼辅因子硫化酶（MOCOS）rs594445基因多态性对硫唑嘌呤所致药品不良反应相关性。方法 招募曾经接受或正在服用硫唑嘌呤的患者,收集静脉血。采用直接测序法测定上述位点基因型,高效液相色谱法检测红细胞中硫唑嘌呤活性代谢产物6-硫鸟嘌呤核苷酸血药浓度,监测患者药品不良反应。结果 80例患者中AOX1 突变杂合子（AG）2例,无纯合突变;MOCOS 突变杂合子（CA）24例,纯合突变（AA）4例;NUDT15突变杂合子（CT）16例,未发现纯合突变。Logistic回归分析表明,MOCOS 突变对硫唑嘌呤所致骨髓抑制有保护性（P =0.012）;与硫唑嘌呤所致流感样症状和脱发相关（P=0.043, 0.030）;NUDT15突变与硫唑嘌呤所致骨髓抑制相关（P=0.012）;其他药品不良反应与上述位点突变无相关性。6-硫鸟嘌呤核苷酸血药浓度在上述位点野生型和突变型之间差异无统计学意义（P>0.05）。NUDT15 rs116855232与MOCOS rs594445联合分析,MOCOS野生型且NUDT15突变型患者发生骨髓抑制的风险会更高（OR=18.40, P=0.001）。结论 硫唑嘌呤首次用药前检测患者MOCOS rs594445和NUDT15 rs116855232基因型,可提高用药安全性。

关键词: 硫唑嘌呤, 醛氧化酶1, 钼辅因子硫化酶, 药品不良反应, 6-硫鸟嘌呤核苷酸, 相关性分析

Abstract: Objective To investigate the association of Aldehyde oxidase 1 (AOX1) rs55754655 and Molybdenum cofactor sulfurase (MOCOS) rs594445 polymorphisms on adverse reactions induced by azathioprine (AZA). Nucleoside diphosphate-linked moiety X-type motif 15(NUDT15) rs116855232 was been as a control site. Methods Patients who had received or were taking azathioprine were recruited to collect venous blood. Direct sequencing was used to determine the genotypes of these sites. High performance liquid chromatography was used to detect serum concentrations of AZA active metabolite 6-thioguanine nucleotide (6-TGN) in erythrocytes. Adverse drug reactions(ADRs) of these patients were monitored. Results In 80 patients, there were 2 mutant heterozygotes(AG) and no homozygous mutations with AOX1. There were 24 mutant heterozygotes(CA) and 4 homozygous mutations(AA) with MOCOS. There were 16 mutant heterozygotes(CT) and no homozygous mutations with NUDT15. Logistic regression analysis showed that the MOCOS mutation was protective for AZA-induced myelosuppression (P=0.012), and it was associated with AZA-induced flu-like symptoms and alopecia (P=0.043, 0.030). There was a significantly correlation between NUDT15 mutation and AZA-induced myelosuppression (P=0.012). There were no correlation between other ADRs and these genes mutations. There was no significant difference between wild type and mutant type of these genes in 6-TGN blood concentration(P>0.05). NUDT15 rs116855232 combined with MOCOS rs594445 analysis, patients with MOCOS wild-type and NUDT15 mutant had a higher risk of myelosuppression (OR=18.40, P=0.001). Conclusion It was suggested that MOCOS rs594445 and NUDT15 rs116855232 polymorphism should be detected bofore the first time use of AZA. It could improve the safety for using AZA.

Key words: azathioprine, aldehyde oxidase1, molybdenum cofactor sulfurase, adverse drug reaction, 6-thioguanine nucleotide

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