Importance of NUDT15 Polymorphisms in Thiopurine Treatments

Abstract

Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 (NUDT15) polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the NUDT15 studies, mainly in Asian countries, and their implementation in several countries.

Autoimmune myositis—Mechanism and therapy development

“…As pulmonary fibrosis can develop secondary to MTX use, its use for patients with ILD should be avoided. In Asians, the NUDT15 polymorphism (c.415C>T, p.R139C) is a common variant that induces severe myelosuppression and hair loss due to AZT; it is recommended to be checked before administration 113 . Renal function should be carefully monitored in patients receiving calcineurin inhibitors (CyA and TAC).…”

“…In Asians, the NUDT15 polymorphism (c.415C>T, p.R139C) is a common variant that induces severe myelosuppression and hair loss due to AZT; it is recommended to be checked before administration. 113 Renal function should be carefully monitored in patients receiving calcineurin inhibitors (CyA and TAC). In addition, postural hand tremor is a relatively common complication of the agents and most evident at peak concentrations.…”

Development of Novel Mass Spectrum-Based Assay for Simultaneous Detection of 36 Variants in the 14 Pharmacogenetic Genes for the Japanese Population

“…6,7) The c.415C > T (p.R139C) in the NUDT15 gene is also associated with thiopurine tolerance, especially in Asian populations. 8) Currently, there are three genes (UGT1A1 for irinotecan safety, NUDT15 for thiopurines safety, and CYP2C9 for siponimod administration) that their variant analyses are covered by national medical insurance in Japan.…”

Advances in Personalized Medicines along with Functional Genomics and Pharmacogenomics

“…Original research papers consist of genetic discovery and functional characterization of CYP1A2 and CYP2C9 [ 1 , 2 ], genetic studies of oral cancer [ 3 , 4 , 5 ], chronic obstruction pulmonary disease (COPD) [ 6 ], asthma [ 7 ], diabetic kidney disease [ 8 ], and web-based pharmacogenomics tool development [ 9 ]. Review papers include the thiopurine treatments with NUDT15 polymorphisms [ 10 ], lipid lowering therapies in familial hypercholesterolemia [ 11 ], incorporation of genetic addiction risk severity (GARS) to overcome the addiction pandemic [ 12 ], and the latest update on genetic variants of UGT [ 13 ] and SULT genes [ 14 ]. The case report includes pharmacogenomics of allopurinol and sulfamethoxazole/Trimethoprim [ 15 ].…”

“…However, since the frequency of TPMT genetic variants used as predictive markers for adverse drug reactions is quite low in Asians, its application in Asians is very limited. Yoshiro Saito’s group [ 10 ] described the recent update of nudix hydrolase 15 (NUDT15) genetic information with thiopurine-induced side effects and its application in Asian races. UGT enzyme is a representative phase II enzyme group and plays an important role in the metabolism of fatty acids, hormones, and drugs.…”