硫唑嘌呤致AOX1和MOCOS基因型药品不良反应相关性分析

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

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NUDT15rs116855232基因型,可提高用药安全性。

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.