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Predictive role of ITPA genetic variants in thiopurine-related myelotoxicity in Crohn’s disease patients

The Pharmacogenomics Journal volume 24, Article number: 20 (2024) Cite this article

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Abstract

Thiopurines, an effective therapy for Crohn’s disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.

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Fig. 1: Simplified pathway of thiopurine metabolism.
Fig. 2: Kaplan–Meier curve depicting cumulative adverse event-free survival of patients under thiopurine treatment according to ITPA gene.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Author information

Author notes

  1. These authors contributed equally: Juliana Salazar, Pau Riera.

Authors and Affiliations

  1. Translational Medical Oncology Laboratory, Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain

    Juliana Salazar

  2. Pharmacy Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain

    Pau Riera

  3. CIBERER U-705, Barcelona, Spain

    Pau Riera

  4. IBD Unit Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Jordi Gordillo, Miguel Martínez, Jordina Llaó, Antonio Giordano & Esther Garcia-Planella

  5. Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain

    Jordi Gordillo, Antonio Giordano & Esther Garcia-Planella

  6. Hematology Department, Fundació Althaia, Manresa, Barcelona, Spain

    Albert Altès

  7. Emergency Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Montserrat Serès

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Contributions

JS and PR contributed to the design of the study, wrote the report, and analyzed data. JG, AA, MM, MS, and JL contributed to extracting and analyzing data and interpreting results. AG and EGP contributed to the design of the study, and analysis of data, and reviewed the final report.

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Correspondence to Antonio Giordano.

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Salazar, J., Riera, P., Gordillo, J. et al. Predictive role of ITPA genetic variants in thiopurine-related myelotoxicity in Crohn’s disease patients. Pharmacogenomics J 24, 20 (2024). https://doi.org/10.1038/s41397-024-00341-2

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