Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease

Tavano, Francesca; Palmieri, Orazio; Latiano, Maria; Gioffreda, Domenica; Latiano, Tiziana; Guerra, Maria; Martino, Giuseppina; Valvano, Maria Rosa; Bossa, Fabrizio; Perri, Francesco; Latiano, Anna

doi:10.3390/ijms26167860

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Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease

by

Francesca Tavano

^1,*

,

Orazio Palmieri

¹

,

Maria Latiano

¹,

Domenica Gioffreda

¹,

Tiziana Latiano

¹,

Maria Guerra

¹,

Giuseppina Martino

¹

,

Maria Rosa Valvano

²

,

Fabrizio Bossa

¹

,

Francesco Perri

¹

and

Anna Latiano

¹

Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, Viale Cappuccini 1, 71013 San Giovanni Rotondo, Italy

²

Quality and Accreditation Unit, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(16), 7860; https://doi.org/10.3390/ijms26167860

Submission received: 13 June 2025 / Revised: 30 July 2025 / Accepted: 8 August 2025 / Published: 14 August 2025

(This article belongs to the Special Issue Molecular Insights on Drug Discovery, Design, and Treatment)

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Abstract

Thiopurines are employed in inflammatory bowel diseases (IBDs; Crohn’s disease, CD; ulcerative colitis, UC) to induce remission, prevent relapse, and reduce the steroid dosage, although they can sometimes be ineffective and present side effects. Genetic variations in the TPMT and NUDT15 genes are well recognized to influence the therapeutic response, despite notable regional differences in their frequencies across various ethnic populations. Herein, the risk haplotypes TPMT*3A, *3B, *3C, and the variant NUDT15*3 were examined in a retrospective cohort of 383 Italian IBD patients who received azathioprine or 6-mercaptopurine. TPMT and NUDT15 genotyping was performed by Sanger sequencing and TaqMan allelic discrimination, respectively. Allelic and genotype frequencies and genotype–phenotype correlations in non-responder and intolerant patients were assessed in comparison to responders. In total, 17% of patients did not respond to treatment, while 20% experienced adverse events, with leukopenia found in 13% of patients. TPMT haplotypes were found in 3.1% of patients, and 1.6% had the NUDT15*3 variant. CD patients with leukopenia had a higher frequency of the TPMT risk haplotype (40% vs. 4%, p = 0.024). Although additional validation through larger prospective studies or meta-analyses is needed, our findings support the importance of TPMT gene-variant assessment for forecasting azathioprine-related leukopenia in Italian IBD patients.

Keywords: inflammatory bowel diseases; thiopurines; toxicity; pharmacogenetics; genotyping; TPMT; NUDT15

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MDPI and ACS Style

Tavano, F.; Palmieri, O.; Latiano, M.; Gioffreda, D.; Latiano, T.; Guerra, M.; Martino, G.; Valvano, M.R.; Bossa, F.; Perri, F.; et al. Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease. Int. J. Mol. Sci. 2025, 26, 7860. https://doi.org/10.3390/ijms26167860

AMA Style

Tavano F, Palmieri O, Latiano M, Gioffreda D, Latiano T, Guerra M, Martino G, Valvano MR, Bossa F, Perri F, et al. Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease. International Journal of Molecular Sciences. 2025; 26(16):7860. https://doi.org/10.3390/ijms26167860

Chicago/Turabian Style

Tavano, Francesca, Orazio Palmieri, Maria Latiano, Domenica Gioffreda, Tiziana Latiano, Maria Guerra, Giuseppina Martino, Maria Rosa Valvano, Fabrizio Bossa, Francesco Perri, and et al. 2025. "Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease" International Journal of Molecular Sciences 26, no. 16: 7860. https://doi.org/10.3390/ijms26167860

APA Style

Tavano, F., Palmieri, O., Latiano, M., Gioffreda, D., Latiano, T., Guerra, M., Martino, G., Valvano, M. R., Bossa, F., Perri, F., & Latiano, A. (2025). Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease. International Journal of Molecular Sciences, 26(16), 7860. https://doi.org/10.3390/ijms26167860

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Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease

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