Comprehensive characterization of pharmacogenetic variants in TPMT and NUDT15 in children with acute lymphoblastic leukemia.

IF 1.7 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pharmacogenetics and genomics Pub Date : 2022-02-01 DOI:10.1097/FPC.0000000000000453
Takaya Moriyama, Wenjian Yang, Colton Smith, Ching-Hon Pui, William E Evans, Mary V Relling, Smita Bhatia, Jun J Yang
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引用次数: 7

Abstract

Thiopurines [e.g. 6-mercaptopurine (6MP)] are essential for the cure of acute lymphoblastic leukemia (ALL) but can cause dose-limiting hematopoietic toxicity. Germline variants in drug-metabolizing enzyme genes TPMT and NUDT15 have been linked to the risk of thiopurine toxicity. However, the full spectrum of genetic polymorphism in these genes and their impact on the pharmacological effects of thiopurines remain unclear. Herein, we comprehensively sequenced the TPMT and NUDT15 genes in 685 children with ALL from the Children's Oncology Group AALL03N1 trial and evaluated their association with 6MP dose intensity. We identified 6 and 5 coding variants in TPMT and NUDT15 respectively, confirming the association at known pharmacogenetic variants. Importantly, we discovered a novel gain-of-function noncoding variants in TPMT associated with increased 6MP tolerance (rs12199316), with independent validation in 380 patients from the St. Jude Total Therapy XV protocol. Located adjacent to a regulatory DNA element, this intergenic variant was strongly associated TPMT transcription, with the variant allele linked to higher expression (P = 2.6 × 10-9). For NUDT15, one noncoding common variant, rs73189762, was identified as potentially related to 6MP intolerance. Collectively, we described pharmacogenetic variants in TPMT and NUDT15 associated with thiopurine sensitivity, providing further insights for implementing pharmacogenetics-based thiopurine individualization.

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急性淋巴细胞白血病儿童TPMT和NUDT15药物遗传变异的综合表征。
硫嘌呤[如6-巯基嘌呤(6MP)]对治疗急性淋巴细胞白血病(ALL)至关重要,但可引起剂量限制性造血毒性。药物代谢酶基因TPMT和NUDT15的种系变异与硫嘌呤毒性的风险有关。然而,这些基因的全谱遗传多态性及其对硫嘌呤药理作用的影响尚不清楚。在此,我们对来自儿童肿瘤组AALL03N1试验的685例ALL患儿的TPMT和NUDT15基因进行了全面测序,并评估了它们与6MP剂量强度的关系。我们分别在TPMT和NUDT15中发现了6个和5个编码变异,证实了已知药物遗传变异的相关性。重要的是,我们在TPMT中发现了一种新的功能获得性非编码变异,与6MP耐受性增加相关(rs12199316),并在St. Jude Total Therapy XV方案的380例患者中进行了独立验证。该基因间变异位于一个调控DNA元件附近,与TPMT转录密切相关,变异等位基因与更高的表达相关(P = 2.6 × 10-9)。对于NUDT15,一个非编码的常见变体rs73189762被确定为可能与6MP不耐受相关。总的来说,我们描述了与硫嘌呤敏感性相关的TPMT和NUDT15的药物遗传变异,为实现基于药物遗传学的硫嘌呤个体化提供了进一步的见解。
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来源期刊
Pharmacogenetics and genomics
Pharmacogenetics and genomics 医学-生物工程与应用微生物
CiteScore
3.20
自引率
3.80%
发文量
47
审稿时长
3 months
期刊介绍: ​​​​Pharmacogenetics and Genomics is devoted to the rapid publication of research papers, brief review articles and short communications on genetic determinants in response to drugs and other chemicals in humans and animals. The Journal brings together papers from the entire spectrum of biomedical research and science, including biochemistry, bioinformatics, clinical pharmacology, clinical pharmacy, epidemiology, genetics, genomics, molecular biology, pharmacology, pharmaceutical sciences, and toxicology. Under a single cover, the Journal provides a forum for all aspects of the genetics and genomics of host response to exogenous chemicals: from the gene to the clinic.
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