Clinical Trials Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2018; 24(8): 941-948
Published online Feb 28, 2018. doi: 10.3748/wjg.v24.i8.941
Comparison of TPMT and NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease
Hong-Hui Wang, Ying He, Hong-Xian Wang, Cheng-Ling Liao, Yu Peng, Li-Jian Tao, Wei Zhang, Hui-Xiang Yang
Hong-Hui Wang, Ying He, Yu Peng, Hui-Xiang Yang, Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Hong-Xian Wang, Department of Anesthesiology, Kunming Angel Women’s & Children’s Hospital, Kunming 650000, Yunnan Province, China
Cheng-Ling Liao, Wei Zhang, Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Li-Jian Tao, Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Author contributions: Wang HH, Yang HX and Tao LJ designed the study; Wang HH, He Y and Wang HX collected the samples; Wang HH, Zhang W and Liao CL performed the DNA extraction and detected the gene polymorphisms; Wang HH, Yang HX, He Y and Wang HX performed follow-up visits; Wang HH, Peng Y, Yang HX and Tao LJ performed the data analysis and interpretation; Wang HH, He Y, Wang HX and Peng Y drafted the manuscript; Yang HX revised the manuscript critically.
Supported by National Natural Science Foundation of China, No. 81370547 and No. 81400642.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Xiangya Hospital, Central South University, Changsha, China.
Clinical trial registration statement: Registration No. ChiCTR-OOC-17010617.
Informed consent statement: Written informed consent was obtained from all the participants.
Conflict-of-interest statement: The authors declare no competing financial interests related to this study.
Open-Access: This article is an open-access article which 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/
Correspondence to: Hui-Xiang Yang, PhD, Professor, Department of Gastroenterology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China. yang_hx430@csu.edu.cn
Telephone: +86-731-84327106 Fax: +86-731-88879602
Received: December 24, 2017
Peer-review started: December 25, 2017
First decision: January 4, 2018
Revised: January 15, 2018
Accepted: January 18, 2018
Article in press: January 18, 2018
Published online: February 28, 2018
Processing time: 64 Days and 23.6 Hours
Abstract
AIM

To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD).

METHODS

This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.

RESULTS

There were 219 patients with IBD (160 men and 59 women), including 39 who were confirmed with ulcerative colitis (UC), 176 with Crohn’s disease (CD) and 4 with undetermined IBD (UIBD). There were 44 patients (20.1%) with mutant genotype of NUDT15 (C/T); among them, 16 received AZA, and 8 (50%) developed leukopenia. There were 175 patients (79.7%) with wild genotype of NUDT15 (C/C); among them, 64 received AZA, and 11 (17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C (P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G (1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients (98.6%) were found to bear the wild genotype of TPMT (A/A); among them, 79 patients received AZA, and 18 (22.8%) developed leukopenia, and there was no significant difference from those with A/G (P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1% (P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.

CONCLUSION

Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.

Keywords: NUDT15; TPMT; Azathioprine; Leukopenia; Inflammatory bowel disease; Individualized therapy

Core tip: Azathioprine (AZA) plays an important role in the remission maintenance therapy of inflammatory bowel disease (IBD). However, serious drug adverse reactions, especially leukopenia, limit its clinical application. European consensus has identified TPMT polymorphism as a predictor of AZA-induced leukopenia. However, the predictive value of TPMT is controversial in Asians with low mutation rate and effectiveness. NUDT15 polymorphism has recently been found to be strongly associated with AZA-induced leukopenia in Asians but there are few data in Chinese populations. This study aimed to observe TPMT and NUDT15 polymorphisms and compare their predictive value for AZA-induced leukopenia in Chinese IBD patients.