2026-04-14T08:39:00Zhttps://recercat.cat/oai/request
oai:recercat.cat:10230/728952026-03-26T20:42:42Zcom_2072_6col_2072_452952
RECERCAT author Tejera-Pérez, Hugo author Márquez, Lucía author Gonzalez-Neira, Anna author ENEIDA Project of GETECCU 2026-03-26T20:42:42Z 2026-03-26T20:42:42Z 2026-03-25T07:33:04Z2026-03-25T07:33:04Z20252026-03-25T07:33:04Z https://hdl.handle.net/10230/72895 Thiopurines (azathioprine and mercaptopurine) are immunosuppressant drugs widely used for the treatment of acute lymphocytic leukemia, organ transplantation and autoimmune diseases, including inflammatory bowel diseases. Thiopurine-induced myelotoxicity (TIM) remains a significant concern in thiopurine therapy, with around 50 % of cases lacking explanation through known genetic variants in thiopurine methyltransferase (TPMT) or nudix (nucleoside diphosphate linked moiety X)-type motif 15 (NUDT15). For these patients, genetic influence remains unknown. In this study, we aim to investigate the potential role of rare deleterious coding variants in TIM development in patients whose toxicities are not explained by either TPMT or NUDT15 genetics. A cohort of 140 thiopurine-treated patients with inflammatory bowel disease from the prospectively maintained ENEIDA registry of GETECCU, comprising 49 TIM-affected and 91 thiopurine tolerant patients was analyzed by whole exome sequencing (WES) and selected a virtual panel of 32 candidate genes belonging to the thiopurine metabolic pathway and other TIM-related genes previously described in the literature. Gene-based analysis revealed an accumulation of rare deleterious variants in XDH among patients who developed TIM (P = 3.7 ×10). Functional analysis highlighted four rare genetic variants that reduce XDH activity. Patients harboring any of these variants exhibited a significantly higher TIM risk (P = 0.032). These findings underscore the importance of considering rare genetic variants, particularly in xanthine dehydrogenase (XDH), in TIM susceptibility and open new opportunities for optimizing treatment efficacy and safety in clinical practice for IBD patients beyond the well-established TPMT and NUDT15 genetics. © 2025 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Azathioprine Bone marrow suppression Crohn's disease GWAS Gene-based analysis Inflammatory bowel disease Mercaptopurine Myelotoxicity NUDT15 TPMT Thiopurine Ulcerative colitis XDH New insights into thiopurine toxicity: The contribution of rare XDH variants to myelotoxicity info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion