摘要
目的:探讨硫唑嘌呤甲基转移酶(thiopurine S-methyltransferase,TPMT)和三磷酸肌苷焦磷酸酶(inosine triphosphate pyrophosphatase,ITPA)基因多态性联合硫鸟嘌呤核苷酸(6-guanine nucleotides,6-TGNs)血药浓度监测与硫唑嘌呤(azathioprine,AZA)治疗系统性红斑狼疮(systemic lupus erythematosus,SLE)所致不良反应的关系。方法:选取2014年5月—2018年4月入住肾病风湿科的103例SLE患者为研究对象,采用聚合酶链式反应(polymerase chain reaction,PCR)、一代测序法检测TPMT和ITPA的基因多态性,高效液相色谱法(high performance liquid chromatography,HPLC)检测红细胞中6-TGNs的血药浓度,并监测患者的不良反应情况。结果:103例患者TPMT有7例突变杂合子(*2 2例、*3A 4例、*3C 1例),无纯合突变。ITPA(94C> A)的CA型10例,AA型0例; ITPA(IVS2+21A> C)的AC型32例,CC型3例。6-TGNs的平均浓度为(338. 5±192. 6) pmol·(8×10~8)~(-1),6-TGNs的浓度在TPMT基因野生型和突变型之间存在明显差异(P <0. 05),但与ITPA基因突变不相关(P均> 0. 05)。Logistic回归分析表明,发生AZA所致的血液学毒性与TPMT突变相关,发生AZA所致的消化系统不良反应和ITPA(IVS2+21A> C)基因突变相关,其他不良反应与TPMT和ITPA突变无相关性。结论:AZA首次用药前,建议检测患者的TPMT和ITPA基因多态性,用药7 d后进行6-TGNs血药浓度检测,可指导临床医师用药,提高用药的安全性。
Objective: To investigate the relationship between thiopurine S-methyltransferase( TPMT),inosine triphosphate pyrophosphatase( ITPA) genetic polymorphisms and blood concentration of 6-guanine nucleotides( 6-TGNs) and azathioprine( AZA) related adverse drug reactions in systemic lupus erythematosus( SLE) patients receiving maintenance therapy. Methods: The total of 103 patients with SLE were admitted to the department of nephrology & rheumatology in our hospital from May 2014 to April 2018. TPMT and ITPA genes were detected by polymerase chain reaction( PCR)-Sanger sequencing. The concentrations of 6-TGNs in red blood cells were measured by high-performance liquid chromatography( HPLC). Results: In 103 patients,there were 7 mutant heterozygotes( * 2 for 2 cases,* 3 A for 4 cases,and * 3 C for 1 case) and no homozygous mutations with TPMT.There were 10 cases of CA type and 0 cases of AA type for ITPA( 94 C > A). There were 32 cases of AC type and3 cases of CC type for ITPA( IVS2 + 21 A > C). The average concentration of 6-TGNs was( 338. 5 ± 192. 6)pmol·( 8 × 10~8)~(-1). The concentration of 6-TGNs was significantly different between wild type and mutant type ofTPMT gene( P < 0. 05),but not related to ITPA gene mutation( P > 0. 05). Logistic regression analysis showed that hematological toxicity induced by AZA was associated with TPMT mutation,ADR induced by AZA was associated with ITPA( IVS2 + 21 A > C) gene mutation,and the other adverse reactions were not associated with TPMT and ITPA mutation. Conclusion: TPMT and ITPA gene polymorphism should be detected before the first time use of AZA. It was suggested that the concentration of 6-TGNs in red blood cells be detected after 7 days of treatment. It can guide physicians for the use of AZA and improve its safety.
引文
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