Published online Feb 28, 2018. doi: 10.3748/wjg.v24.i8.941
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
To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine (AZA)-induced leukopenia in inflammatory bowel disease (IBD).
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.
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.
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.
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.