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Association of ITPA gene polymorphisms with adverse effects of AZA/6-MP administration: a systematic review and meta-analysis

The Pharmacogenomics Journal volume 22, pages 39–54 (2022)Cite this article

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Abstract

Azathioprine (AZA) and its metabolite, mercaptopurine (6-MP), are widely used immunosuppressant drugs. Polymorphisms in genes implicated in AZA/6-MP metabolism, reportedly, could account in part for their potential toxicity. In the present study we performed a systematic review and a meta-analysis, comprising 30 studies and 3582 individuals, to investigate the putative genetic association of two inosine triphosphatase (ITPA) polymorphisms with adverse effects in patients treated with AZA/6-MP. We found that rs1127354 is associated with neutropenia in general populations and in children (OR: 2.39, 95%CI: 1.97–2.90, and OR: 2.43, 95%CI: 2.12–2.79, respectively), and with all adverse effects tested herein in adult populations (OR: 2.12, 95%CI: 1.22–3.69). We also found that rs7270101 is associated with neutropenia and leucopenia in all-ages populations (OR: 2.93, 95%CI: 2.36–3.63, and OR: 2.82, 95%CI: 1.76–4.50, respectively) and with all adverse effects tested herein in children (OR: 1.74, 95%CI: 1.06–2.87). Stratification according to background disease, in combination with multiple comparisons corrections, verified neutropenia to be associated with both polymorphisms, in acute lymphoblastic leukemia (ALL) patients. These findings suggest that ITPA polymorphisms could be used as predictive biomarkers for adverse effects of thiopurine drugs to eliminate intolerance in ALL patients and clarify dosing in patients with different ITPA variants.

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Fig. 1: PRISMA flow diagram.
Fig. 2: Influence of rs1127354 in AZA/6-MP adverse effects.
Fig. 3: Influence of rs7270101 in AZA/6-MP adverse effects.

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Funding

PIK and PGB acknowledge support of this work by the project “ELIXIR-GR: The Greek Research Infrastructure for Data Management and Analysis in Life Sciences”, Grant Number (MIS) 5002780.

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  1. Department of Computer Science and Biomedical Informatics, University of Thessaly, 2-4 Papasiopoulou str, 35131, Lamia, Greece

    Evaggelia Barba, Panagiota I. Kontou, Pantelis G. Bagos & Georgia G. Braliou

  2. Center of Systems Biology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Efessiou, 11527, Athens, Greece

    Ioannis Michalopoulos

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GGB participated in the conception of the study, in data collection, in the analysis and in the interpretation of the results. PGB participated in the conception of the study, in data collection, in the analysis and in the interpretation of the results. EB did most of data collection, performed most of the analysis, participated in the interpretation of the results, and drafted the initial version of the manuscript. PIK participated in the analysis and in interpretation of the results. IM participated in the interpretation of the results. All authors participated in drafting the manuscript. All authors read and approved the final version of the manuscript.

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Barba, E., Kontou, P.I., Michalopoulos, I. et al. Association of ITPA gene polymorphisms with adverse effects of AZA/6-MP administration: a systematic review and meta-analysis. Pharmacogenomics J 22, 39–54 (2022). https://doi.org/10.1038/s41397-021-00255-3

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