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
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.
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.
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.
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.
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).
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.
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.