| DOI: 10.29090/psa.2026.01.25.5153 | Pharm Sci Asia 2026; 53(1), 11-22 |
Impact of NUDT15 polymorphisms on myelosuppression in Thai patients with autoimmune diseases undergoing azathioprine therapyKanyarat Khaeso1, Chingching Foocharoen2, Ajanee Mahakkanukrauh2, Chinadol Wanitpongpun2, Siraphop Suwannaroj2, Nontaya Nakkam1, Suda Vannaprasaht1, Areerat Dornsena1, Wichittra Tassaneeyakul1*
1 Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand
2 Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand
Azathioprine (AZA) is an immunosuppressive drug widely used to treat autoimmune diseases but poses a significant risk of myelosuppression. Genetic polymorphisms affecting AZA metabolism, particularly in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), thiopurine S-methyltransferase (TPMT), inosine triphosphatase (ITPA), and ATP-binding cassette sub-family C member 4 (ABCC4), may influence this risk. This study aimed to evaluate the impact of NUDT15, TPMT, ITPA, ABCC4 polymorphisms on AZA-induced myelosuppression in Thai patients with autoimmune diseases. A total of 125 Thai patients receiving AZA were enrolled. Genotyping of NUDT15, TPMT, ITPA, and ABCC4 polymorphisms was performed, and phenotypes were inferred from genotype data. Clinical and laboratory parameters were monitored for one year following AZA initiation. Among 125 patients, 19 (15.2%) developed AZA-induced leukopenia. NUDT15 polymorphisms showed the strongest association with leukopenia risk. Intermediate metabolizer (IM) and poor metabolizer (PM) phenotypes of NUDT15 were significantly associated with increased leukopenia risk, with odds ratios of 8.57 (95% CI 2.37–31.07, P = 0.001) and 30.00 (95% CI 2.82–319.20, P = 0.005) compared with the normal metabolizer (NM). No significant associations were observed for TPMT, ITPA, or ABCC4 polymorphisms. Patients with IM NUDT15 exhibited significantly lower final white blood cell counts and required lower average AZA doses. Therefore, NUDT15 polymorphisms are key determinants of AZA-induced leukopenia in Thai patients. Early identification of NUDT15 polymorphism allows personalized dosing strategies, reducing the risk of AZA-induced myelosuppression.
Keyword:
Autoimmune diseases; Azathioprine; Leukopenia; Myelosuppression; NUDT15
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