Pharmacogene Variation Consortium Gene Introduction: NUDT15
Pharmacogene Variation Consortium Gene Introduction: NUDT15
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DOI：
10.1002/cpt.1268
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发表时间：
2019-05-01
影响因子：
6.7
通讯作者：
Gaedigki, Andrea
中科院分区：
文献类型：
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作者：
Yang, Jun J.;Whirl-Carrillo, Michelle;Gaedigki, Andrea
Pharmacogene Variation (PharmVar) 联盟是人类细胞色素 P450 (CYP) 等位基因命名网站的继承者，该网站通过指定 CYP 星号 (*) 等位基因为药物遗传学界提供服务。 PharmVar 的目标是继续履行作为全球药物遗传学界官方等位基因指定权威的使命。 1 在此，我们描述了将第一个非 CYP 基因引入 PharmVar。 NUDT15 的药物遗传学变异在硫嘌呤反应变异性和毒性中起着重要作用。 NUDT15 基因 NUDT15 是一个大磷酸酶蛋白家族的成员，该家族共享一个共同的 NUDIX 催化结构域并代谢多种核苷酸底物（表 1）。 NUDT15 最初被定性为焦磷酸酶，可将氧化的 GTP 转化为其单磷酸盐形式，从而阻止受损的嘌呤核苷酸整合到 DNA 中以及随后的错配修复。然而，与NUDT15的主要代谢物NUDT1相比，8-oxo-GTP是NUDT15的弱底物；因此，NUDT15的生理功能仍不清楚。在药物毒性的全基因组关联研究中，NUDT15已与异生药物代谢联系起来，随后的机制研究表明，它在活性硫嘌呤代谢物三磷酸硫鸟苷向单磷酸硫鸟苷的转化中发挥着关键作用。 2 编码无功能或严重降低功能的 NUDT15 变异体在接受此类药物治疗良性（例如炎症性肠病）或恶性（例如急性淋巴细胞白血病）病症时使患者容易出现硫嘌呤过度激活和造血毒性。鉴于这种药物遗传学关联具有令人信服的基础生物学和临床相关性，人们对预防性 NUDT15 指导的硫嘌呤给药以避免严重不良事件越来越感兴趣。更新的临床药物遗传学实施联盟 (CPIC) 进一步证明了将 NUDT15 遗传信息纳入预防硫嘌呤毒性的剂量建议的重要性
The Pharmacogene Variation (PharmVar) Consortium is the successor of the Human Cytochrome P450 (CYP) Allele Nomenclature website that served the pharmacogenetics community by designating CYP star (*) alleles. The aim of PharmVar is to continue the mission of serving as an official allele designation authority for the global pharmacogenetics community. 1 Herein, we describe the introduction of the first non-CYP gene to PharmVar. Pharmacogenetic variation of NUDT15 plays a significant role in thiopurine response variability and toxicity.THE NUDT15 GENE NUDT15 is a member of a large phosphatase protein family that shares a common NUDIX catalytic domain and metabolizes a wide range of nucleotide substrates (Table 1). Originally characterized as a pyrophosphatase, NUDT15 converts oxidized GTP to its monophosphate form, preventing the integration of the damaged purine nucleotides into DNA and subsequent mismatch repair. However, 8-oxo-GTP is a weak substrate for NUDT15 compared with its main metabolizer NUDT1; thus, the physiological functions of NUDT15 remain unclear. NUDT15 has been linked to xenobiotic drug metabolism in genome-wide association studies of drug toxicity, and subsequent mechanistic studies have demonstrated that it plays a key role in the conversion of the active thiopurine metabolite thioguanosine triphosphate to thioguanosine monophosphate. 2 NUDT15 variants encoding no or severely decreased function predispose patients to excessive thiopurine activation and hematopoietic toxicities when receiving this class of drugs for either benign (eg, inflammatory bowel diseases) or malignant (eg, acute lymphoblastic leukemia) conditions. Given the compelling underlying biology and clinical relevance of this pharmacogenetic association, there is a growing interest in preemptive NUDT15-guided thiopurine dosing to avoid severe adverse events. The importance of including NUDT15 genetic information in dosing recommendations for preventing thiopurine toxicity is further evidenced by the updated Clinical Pharmacogenetics Implementation Consortium (CPIC)