背景:硫嘌呤药物是炎症性肠病和其他疾病的有效治疗选择,但在一些患者中由于毒性而停用。
方法:我们利用一组46个基因的外显子组测序数据,研究了小儿炎症性肠病队列中硫嘌呤诱导的毒性,包括TPMT和NUDT15。
结果:该队列包括487名患者,中位年龄为13.1岁。在396名暴露于硫嘌呤的患者中,在11%中观察到骨髓抑制,胃肠病学不耐受占11%,肝毒性在4.5%,胰腺炎占1.8%,和“其他”不良反应占2.8%。TPMT(硫嘌呤S-甲基转移酶)酶活性正常87.4%,中级12.3%,不足0.2%;26%的中等活性患者对硫嘌呤产生毒性。在28例(7%)患者中发现了与酶活性缺陷相关的常规基因分型的TPMT等位基因:TPMT*3A占4.5%,*3B在1%,和*3C为1.5%。其中,只有6例(21%)患者出现毒性反应.三个罕见的TPMT等位基因(*3D,*39和*40)未对3例患者进行常规基因分型评估,他们都产生了毒性反应。在4例患者(硫唑嘌呤1.6mg/kg/d)中发现了错义变异p.R139C(NUDT15*3等位基因),但只有1发展毒性。NUDT15中一名患有框内缺失变体p.G13del的患者在低剂量时出现骨髓抑制。每基因有害性评分GenePy鉴定了AOX1和DHFR基因中毒性的显著关联。
结论:在对TPMT和NUDT15变体呈阴性的个体中,在AOX1和DHFR基因中观察到与毒性的显著关联。携带NUDT15*3等位基因的患者,这与骨髓抑制有关,没有显示毒性风险增加。
本研究报道了硫嘌呤在小儿炎症性肠病患者中引起的毒性。这些发现是在遗传变异的背景下提出的,关注与硫嘌呤药物代谢有关的基因,从而导致患者出现毒性的药物基因组关联缺失。
BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity.
METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15.
RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to
thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and \"other\" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to
thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes.
CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.
This study reports thiopurine-induced toxicity in pediatric patients with inflammatory bowel disease. The findings are presented in the context of genetic variations, focusing on genes implicated in thiopurine drug metabolism, thereby contributing to the missing pharmacogenomic association in patients developing toxicity.