title: Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose.
abstract: Thiopurines are widely used as anticancer and immunosuppressive agents. However, life-threatening myelotoxicity has been noticed and largely explained by genetic variations, including NUDT15 polymorphisms (e.g., rs116855232). In this study, we conduct a meta-analysis to investigate the impact of rs116855232 on thiopurines-induced myelotoxicity susceptibility (1752 patients from 7 independent cohorts), as well as on thiopurines intolerance dose (2745 patients from 13 cohorts). Variant allele of rs116855232 contributes 7.86-fold (P < 0.00001, 95% CI: 6.13-10.08) higher risk to develop leucopenia with high specificity (91.74%) and sensitivity (43.19%), and lower thiopurines intolerance dose (P < 0.00001). Through bioinformatics prediction, amino acid changes induced by genetic variants are considered to reduce the stability, and break an α helix of NUDT15, which is part of the thiopurine binding pocket. Additionally, we conduct an expression quantitative trait loci (eQTL) analysis for NUDT15, and find a promoter-located eQTL signal (rs554405994), which may act as a potential marker to predict thiopurines-induced myelotoxicity. In conclusion, genetic polymorphisms in NUDT15 are strongly associated with adverse drug reaction (ADR) of thiopurines, although more evidences are needed to determine values of all functional NUDT15 polymorphisms for clinical regimen, rs116855232 should be considered as a highly credible pharmacogenetic indicator for thiopurines using espcially is Asians.
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Yin
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Junlong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Shouyue
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liao
authors.affiliation: Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Oncology, Cancer Center, National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Hou
authors.affiliation: Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.affiliation: Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Precision Medicine, China-Japan Friendship Hospital, Beijing, China.
authors.forename: Heyao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yuelan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.|Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shu
mesh_terms: D004342:Drug Hypersensitivity / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D000096964:Nudix Hydrolases
chemical_list: D011755:Pyrophosphatases; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases
keywords: NUDT15; intolerance dose; meta-analysis; thiopurines-induced myelotoxicity