Gazouli Muaria, Pachoula Ioanna, Panayotou Ioanna, Chouliaras Georgios, Anagnou Nicholas P, Chroussos George, Roma Eleftheria
Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, (Maria Gazouli, Nicholas P. Anagnou).
First Department of Pediatrics, "Aghia Sophia" Children's Hospital, School of Medicine, University of Athens (Ioanna Pachoula, Ioanna Panayotou, Georgios Chouliaras, George Chroussos, Eleftheria Roma).
Ann Gastroenterol. 2012;25(3):249-253.
Azathioprine (AZA) and 6-mercaptopurine (6MP) are used in the treatment of pediatric inflammatory bowel disease (IBD). Genetic variations in thiopurine S-methyltranfarase (TPMT) gene have been correlated with enzyme activity and with the occurrence of adverse events to AZA and 6MP. The aim of the present study was to examine the sensitivity and specificity of genotyping for TPMT enzymatic activity, reducing harm from thiopurine by pretesting, and the association of thiopurine toxicity with TPMT status in children with IBD.
TPMT red blood cell (RBC) activity was measured by using a radiochemical method and genotype was determined for the *2, *3A, *3B and *3C in 108 thiopurinetreated pediatric IBD patients with a mean age of 11.3 years (range 3-16).
Significant TPMT activity differences between wild-type and heterozygous and homozygous mutated subjects were observed. We divided TPMT activity into three categories according to frequency distribution: low (16.67%), intermediate (25.92%) and high (57.41%). The whole population included a total of 77.78% of homozygous wild-type subjects, 15.74% heterozygous variants, 1.85% homozygous variants and five (4.63%) compound heterozygous variant *3B/*3C. The overall concordance rate between genotypes and phenotypes was 88.2%. Seven carriers of at least one variant allele and low or intermediate TPMT activity developed adverse effects.
Our findings suggest that carriers of at least one variant allele and both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelotoxicity compared with individuals with normal genotype and TPMT activity.
硫唑嘌呤（AZA）和6-巯基嘌呤（6MP）用于治疗小儿炎症性肠病（IBD）。硫嘌呤S-甲基转移酶（TPMT）基因的遗传变异与酶活性以及AZA和6MP不良事件的发生相关。本研究的目的是检验TPMT酶活性基因分型的敏感性和特异性，通过预测试减少硫嘌呤的危害，以及IBD患儿中硫嘌呤毒性与TPMT状态的关联。
采用放射化学方法测量108例接受硫嘌呤治疗的小儿IBD患者的TPMT红细胞（RBC）活性，并确定*2、*3A、3B和3C的基因型，这些患者的平均年龄为11.3岁（范围3 - 16岁）。
观察到野生型与杂合子和纯合子突变受试者之间TPMT活性存在显著差异。我们根据频率分布将TPMT活性分为三类：低（16.67%）、中（25.92%）和高（57.41%）。总体人群中纯合野生型受试者占77.78%，杂合变异体占15.74%，纯合变异体占1.85%，5例（4.63%）为复合杂合变异体*3B/*3C。基因型与表型的总体一致性率为88.2%。7例至少携带一个变异等位基因且TPMT活性低或中等的携带者出现了不良反应。
我们的研究结果表明，与基因型和TPMT活性正常的个体相比，至少携带一个变异等位基因且TPMT活性中等或缺乏的携带者发生硫嘌呤诱导的骨髓毒性的风险增加。
