Retrospective Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 14, 2019; 25(38): 5850-5861
Published online Oct 14, 2019. doi: 10.3748/wjg.v25.i38.5850
Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients
Xia Zhu, Kang Chao, Miao Li, Wen Xie, Hong Zheng, Jin-Xin Zhang, Pin-Jin Hu, Min Huang, Xiang Gao, Xue-Ding Wang
Xia Zhu, Hong Zheng, Min Huang, Xue-Ding Wang, Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
Kang Chao, Miao Li, Pin-Jin Hu, Xiang Gao, Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
Wen Xie, Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, United States
Jin-Xin Zhang, School of Public Health, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
Author contributions: Zhu X and Zheng H detected the metabolite concentrations and genotypes; Chao K, Li M, and Gao X enrolled the patients and collected the clinical data; Wang XD and Zhang JX finished the data analysis; Zhu X and Wang XD wrote the manuscript; Hu PJ and Huang M supervised the study; Xie W reviewed this paper.
Supported by the National Natural Science Foundation of China, No. 81573507, No. 81473283, No. 81173131, and No. 81320108027; Guangdong Provincial Key Laboratory Construction Foundation, No. 2017B030314030; The National Key Research and Development Program, No. 2016YFC0905003; and the 111 Project, No. B16047.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare no competing financial interests related to this study.
Data sharing statement: No additional data are available.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Xue-Ding Wang, PharmD, Professor, Teacher, Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132, Waihuan Dong Road, Guangzhou University City, Guangzhou 510000, Guangdong Province, China. wangxd@mail.sysu.edu.cn
Telephone: +86-20-39943027 Fax: +86-20-39943002
Received: July 24, 2019
Peer-review started: July 24, 2019
First decision: August 17, 2019
Revised: September 5, 2019
Accepted: September 11, 2019
Article in press: September 11, 2019
Published online: October 14, 2019
Processing time: 82 Days and 1.9 Hours
Abstract
BACKGROUND

Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?

AIM

To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.

METHODS

Patients’ clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured.

RESULTS

A total of 411 Crohn’s disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively.

CONCLUSION

The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.

Keywords: Crohn’s disease; Thioguanine nucleotide levels; Nucleoside diphosphate-linked moiety X-type motif 15; Thiopurine-induced leukopenia

Core tip: Thiopurine-induced leukopenia (TIL), a life-threatening toxicity in inflammatory bowel disease, occurs with a high frequency in Asia. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly increase the prediction sensitivity of TIL, more than 50% of cases cannot be predicted by this mutation. The potential use of steady-state thioguanine nucleotide (6TGN) levels to predict TIL has been explored for decades, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 genotypes? Yes! According to our research, applying 6TGN levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.