NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects

Abstract

Introduction:Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT∗3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics.Case presentation:A 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered.Conclusion:In this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT∗3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity.

Implementation of NUDT15 Genotyping to Prevent Azathioprine‐Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population

“…Although the association between TPMT polymorphisms and AZA‐induced leukopenia is well‐established, these variants are less common among Asian patients than among White patients, 25,26 and recent studies showed that NUDT15 polymorphisms were associated with thiopurine‐induced toxicity in Asians, including Chinese, Japanese Korean, and Indian populations 5,15,16,27–30 . Preventative screening approaches can be very effective in preventing treatment failure and adverse reactions with severe complications 31,32 .…”

“…Although the association between TPMT polymorphisms and AZA‐induced leukopenia is well‐established, these variants are less common among Asian patients than among White patients, 25 , 26 and recent studies showed that NUDT15 polymorphisms were associated with thiopurine‐induced toxicity in Asians, including Chinese, Japanese Korean, and Indian populations. 5 , 15 , 16 , 27 , 28 , 29 , 30 Preventative screening approaches can be very effective in preventing treatment failure and adverse reactions with severe complications. 31 , 32 Our previous studies have shown important clinical implementations of pharmacogenomic testing to prevent severe adverse drug reactions.…”

Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report

“… 15 Similarly, other studies have also demonstrated an increased risk of thiopurine-induced leukopenia with NUDT15 R139C. 16 - 18 …”

An Updated Review of Genetic Associations With Severe Adverse Drug Reactions: Translation and Implementation of Pharmacogenomic Testing in Clinical Practice

“…In meta-analysis studies, TPMT*3C variant is known to be associated with an increased risk in thiopurine-induced leukopenia in European descendants ( Budhiraja and Popovtzer, 2011 ; Avallone et al, 2014 ; Walker et al, 2019 ). On the other hand, NUDT15 R139C (rs116855232, NUDT15*3) variant carriers are strongly associated with thiopurine-induced leukopenia in Asian populations, including Chinese, Japanese, Korean, and Indian populations ( Tanaka et al, 2015 ; Kakuta et al, 2016 ; Moriyama et al, 2016 ; Kim et al, 2017 ; Fei et al, 2018a ; Fei et al, 2018b ; Banerjee et al, 2020 ).…”