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:
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.
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
Research background

Thiopurine-induced leukopenia (TIL) is life-threatening and occurs with a high frequency in Asia. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants improve the predictive sensitivity of TIL, more than 50% of TIL cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL is controversial.

Research motivation

Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?

Research objectives

To obtain a better model with combination of 6TGN levels and NUDT15 R139C genotypes to predict thiopurine-induced TIL and improve the safety for the thiopurine treatment.

Research methods

A total of 411 patients diagnosed with Crohn’s disease at the Sixth Affiliated Hospital of the Sun Yat-sen University were included in this study. Peripheral blood from patients was collected to detect the NUDT15 R139C/TPMT*3C genotypes and 6TGN concentrations at School of Pharmaceutical Sciences, Sun Yat-sen University. The X2 method or Fisher’s exact test was used to check the association of TIL with NUDT15 R139C/TPMT*3C diplotypes. A receiver operating characteristic (ROC) curve was used to obtain 6TGN cut-off levels to predict the development of TIL.

Research results

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). After comparing the 6TGN levels based on NUDT15 R139C, for CC (n = 342) and CT (n = 65), the median 6TGN level in patients with TIL was significantly higher than that in patients without (P = 9.4 × 10-5, 474.8 pmol/8 × 108 RBC vs 306.0 pmol/8 × 108 RBC and P = 0.039, 291.7 pmol/8 × 108 RBC vs 217.6 pmol/8 × 108 RBC, 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. The area under the ROC curve for the obtained predicted probabilities based on NUDT15 R139C and the 6TGN level was 0.79 (95%CI: 0.76-0.92).

Research conclusions

The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping patients according to NUDT15 R139C genotypes.

Research perspectives

Applying these specific 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 R139C is strongly recommended during the thiopurine treatment.