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:
Correspondence to: Hui-Xiang Yang, PhD, Professor, Department of Gastroenterology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China.
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
Research background

Azathioprine (AZA) plays a key role in remission maintenance therapy of inflammatory bowel disease (IBD), although it causes serious adverse reactions, including leukopenia. TPMT polymorphism is a predictor of AZA-induced leukopenia in Caucasians. However, the predictive value of TPMT is controversial in Asians. NUDT15 polymorphism is a more effective predictor of AZA-induced leukopenia in Asians, but there are few data in Chinese populations.

Research motivation

The purpose of this study was to observe TPMT and NUDT15 polymorphisms and compare their values in predicting AZA-induced leukopenia in Chinese IBD patients.

Research objectives

To find a more valuable predictor of AZA-induced leukopenia in Chinese patients with IBD, improve our ability to manage these patients more safely, and optimize AZA therapy.

Research methods

A total of 219 patients diagnosed with IBD in Xiangya Hospital, Central South University were enrolled. 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. Patients who received AZA underwent routine blood tests and liver function tests once a week. Data analysis was performed by χ2 test, Student’s t test or logistic regression analyses using SPSS version 18.

Research results

We enrolled 219 patients with IBD (160 men and 59 women). 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%) and 1 was treated with AZA and then developed leukopenia. The remaining 216 patients (98.6%) were found to bear the wild genotype of TPMT (A/A); among them, 79 received AZA, and 18 (22.8%) developed leukopenia. There was no significant difference from those with A/Gs (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 for prediction of AZA-induced leukopenia. Moreover, combined use of corticosteroids reduced the risk of AZA-induced leukopenia (P = 0.023, odds ratio (OR) = 0.201, 95% confidence interval (CI): 0.050-0.798, relative risk (RR) = 0.437, preventive fraction (PF) = 0.253) and fewer women than men developed leukopenia after receiving AZA (P = 0.039, OR = 0.146, 95%CI: 0.023-0.909, RR = 0.527, PF = 0.124).

Research conclusions

In Chinese patients with IBD, the mutation rate of NUDT15 is significantly higher than that of TPMT. NUDT15 polymorphism is more strongly associated with AZA-induced leukopenia than TPMT is. Detecting NUDT15 genotype before AZA treatment is more effective at predicting the risk of developing leukopenia than detecting TPMT genotype. Combined use of corticosteroids is a potential way to reduce the risk of leukopenia. Males have a higher risk of developing AZA-induced leukopenia and need to be more closely monitored than females. Further research is necessary to verify this relationship and determine the precise mechanism.

Research perspectives

According to our study, NUDT15 polymorphism may predict AZA-induced leukopenia more effectively than TPMT does. Female sex and corticosteroid usage were negatively associated with developing AZA-induced leukopenia. This might be helpful for AZA-induced leukopenia prevention and to optimize AZA therapy for IBD. While the definite relationship was obscure, more research about how they affect AZA metabolism should be carried out in the future. To learn more about the interaction between them, multicenter studies with larger samples and functional genomics technology may be carried out in future research.