Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study.

Zhao-Yang Chen,Zhi-Yao He,Rui Zhang,Wei-Qiao Shi,Yu Yan,Mi-Ye Wang,Ling-Yan Zhou,Ning-Ning Chao,Zhou Qin,Ting Xu,Bin Wu,Xiao-Jun Lu,Yu-Wen Pei,Ze-Hao Su,Yang-Hui Zhu

doi:10.3389/fphar.2021.672769

Abstract

The aim of this study was to investigate the correlation between genetic polymorphisms of azathioprine-metabolizing enzymes and adverse reactions of myelosuppression. To this end, a retrospective analysis was performed on 1,419 Chinese patients involving 40 different diseases and 3 genes: ITPA (94C>A), TPMT*3 (T>C), and NUDT15 (415C>T). Strict inclusion and exclusion criteria were established to collect the relative cases, and the correlation between azathioprine and myelosuppression was evaluated by adverse drug reaction criteria. The mutation rates of the three genes were 29.32, 3.73, and 21.92% and grades I to IV myelosuppression occurred in 54 (9.28%) of the 582 patients who took azathioprine. The highest proportion of myelosuppression was observed in 5 of the 6 (83.33%) patients carrying the NUDT15 (415C>T) TT genotype and 12 of the 102 (11.76%) patients carrying the NUDT15 (415C>T) CT genotype. Only the NUDT15 (415C>T) polymorphism was found to be associated with the adverse effects of azathioprine-induced myelosuppression (odds ratio [OR], 51.818; 95% CI, 5.280–508.556; p = 0.001), which suggested that the NUDT15 (415C>T) polymorphism could be an influencing factor of azathioprine-induced myelosuppression in the Chinese population. Epistatic interactions between ITPA (94C>A) and NUDT15 (415C>T) affect the occurrence of myelosuppression. Thus, it is recommended that the genotype of NUDT15 (415C>T) and ITPA (94C>A) be checked before administration, and azathioprine should be avoided in patients carrying a homozygous NUDT15 (415C>T) mutation. This study is the first to investigate the association between genetic polymorphisms of these three azathioprine-metabolizing enzymes and myelosuppression in a large number of cases with a diverse range of diseases.

Highlights

Azathioprine (AZA) is a classic immunosuppressant that is widely used for post-transplant rejection, severe rheumatoid arthritis, systemic lupus erythematosus, pemphigus (Joly et al, 2020), inflammatory bowel disease (Ran et al, 2020), dermatomyositis, and other diseases (Mack et al, 2020)
According to the Common Terminology Criteria for Adverse Events (CTCAEs) version 5.0 published by the United States Department of Health and Human Services and the hospital leukocyte count index standard, myelosuppression was defined as a white blood cell count (WBC) count
The inosine triphosphate pyrophosphatase (ITPA) (94C>A), thiopurine S-methyltransferase (TPMT)*3 (T>C), and nucleoside diphosphate-liked moiety X motif 15 (NUDT15) (415C>T) genotype distributions were in Hardy–Weinberg equilibrium (p 0.959, 0.811, and 0.406, respectively)

Summary

Introduction

Azathioprine (AZA) is a classic immunosuppressant that is widely used for post-transplant rejection, severe rheumatoid arthritis, systemic lupus erythematosus, pemphigus (Joly et al, 2020), inflammatory bowel disease (Ran et al, 2020), dermatomyositis, and other diseases (Mack et al, 2020). It is recommended for the treatment of immune checkpoint inhibitor-related renal and musculoskeletal adverse events (Thompson et al, 2020). 6-TGTP binds to Rac, and inactivates it by regulating the Vav-Rac signaling pathway in T lymphocytes; this results in the inhibition of Rac target genes, such as nuclear factor kappa beta (NF-κβ), leading to the increased apoptosis of activated T lymphocytes (Tiede et al, 2003; Poppe et al, 2006) (Supplementary Figure S1)

Objectives

Methods

Results

Discussion

Conclusion