Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose

// Dandan Yin 1, * , Xuyang Xia 1, * , Junlong Zhang 2, * , Shouyue Zhang 1, * , Fei Liao 1 , Ge Zhang 3 , Yan Zhang 4 , Qianqian Hou 1 , Xue Yang 5 , Hong Wang 5 , Zhigui Ma 3 , Heyao Wang 6 , Yiping Zhu 3 , Wei Zhang 7 , Yuelan Wang 1 , Bo Liu 1 , Lanlan Wang 2 , Heng Xu 1, 2 , Yang Shu 1 1 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 2 Department of Laboratory Medicine/Research Center of Clinical Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China 3 Department of Pediatric Hematology/Oncology, West China Second Hospital Sichuan University, Chengdu, Sichuan, China 4 Department of Thoracic Oncology, Cancer Center, National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China 5 Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA 6 Department of Precision Medicine, China-Japan Friendship Hospital, Beijing, China 7 Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, China * These authors contributed equally to this work Correspondence to: Lanlan Wang, email: wangll87@126.com Heng Xu, email: xuheng81916@scu.edu.cn Yang Shu, email: shuyang1986@gmail.com Keywords: meta-analysis, NUDT15, thiopurines-induced myelotoxicity, intolerance dose Received: November 08, 2016      Accepted: January 04, 2017      Published: January 11, 2017 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.