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Influence of TPMT polymorphisms on azathioprine-induced myelosuppression in Bangladeshi patients with systemic lupus erythematosus

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Abstract

Background

Thiopurine methyltransferase (TPMT) enzymes play a crucial role in azathioprine metabolism. Mutations in the enzyme initiate generation of excess thioguanine, which causes suppression of various cell lineages.

Objectives

The objectives of this study were to investigate the prevalence of TPMT mutation in Bangladeshi patients with systemic lupus erythematosus (SLE) requiring azathioprine therapy and its relation to the development of myelosuppression.

Methods

250 patients with SLE were enrolled, then monitored for myelosuppression adverse events for 4 months. TPMT*3C (rs1142345), TPMT*3B (rs1800460), and TPMT*2 (rs1800462) polymorphisms were analyzed using polymerase chain reaction–restriction fragment length polymorphism. The risk of myelosuppression (i.e., leukopenia, thrombocytopenia, and anemia) was estimated as the odds ratio (OR) with 95% confidence intervals (CIs) and p values.

Results

Of the 250 patients, 17 (6.8%) were heterozygous for the TPMT*3 mutation and 233 (93.2%) were homozygous for the wild type; no patients carried a homozygous mutation. Grade III/IV leukopenia, thrombocytopenia, and anemia occurred in 12.0%, 12.0%, and 27.9% of wild-type TPMT patients respectively; corresponding rates in heterozygous TPMT*3C patients were 70.6%, 64.7%, and 5.9%. Patients with Grade III/IV azathioprine-induced leukopenia were significantly more likely to have the heterozygous TPMT*3C genotype than the wild-type variant (OR 17.6; 95% CI 5.8–53.6; p < 0.0001), with comparable results for Grade III/IV azathioprine-induced thrombocytopenia (OR 13.4; 95% CI 4.6–39.2; p < 0.0001).

Conclusion

Patients with SLE carrying the TPMT*3C heterozygous genotype are at risk of azathioprine-induced myelosuppression.

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Acknowledgements

The authors are thankful to the patients, volunteers, nurses, physicians, and scientists of Bangabandhu Sheikh Mujib Medical University (BSMMU). The authors are also thankful to the Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Bangladesh for providing the opportunity to carry out the research work.

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Author notes

  1. Mohammad Mamun Ur Rashid, Imtiaz Ahmed, and Md. Asraful Islam contributed equally.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Health and Life Sciences, North South University, Dhaka, 1129, Bangladesh

    Mohammad Mamun Ur Rashid, Imtiaz Ahmed, Md. Asraful Islam & Hasan Mahmud Reza

  2. Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh

    Tasnova Tasnim, Noor Ahmed Nahid, Mohd Nazmul Hasan Apu, Mir Md. Abdullah Al-Mamun, Md. Reazul Islam, Maizbha Uddin Ahmed & Abul Hasnat

  3. Department of Pharmacy, Noakhali Science and Technology University, Sonapur, Noakhali, 3814, Bangladesh

    Mohammad Safiqul Islam

  4. Department of Biotechnology, Shimane University, Matsue, Japan

    Kazushige Yokota & Mohammad Safiqul Islam

  5. Department of Rheumatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

    Masud Karim & Md. Nazrul Islam

  6. Department of Pharmacy, Faculty of Sciences and Engineering, East West University, Dhaka, Bangladesh

    Tasnova Tasnim

  7. Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh

    Samia Shabnaz

Authors
  1. Mohammad Mamun Ur Rashid
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Contributions

MMUR, IA, and MAI collected samples and carried out the study. TT, NAN, MNHA, MRI, and SS drafted the manuscript. AH, MSI, MUA, KY, and HMR conceived the study design and performed statistical analysis. MMAAM, MK, MNI, and HMR guided the study conducted in laboratory and performed the evaluation. MUA, MSI, KY, and HMR checked the manuscript and suggested improvements. All authors discussed, provided conceptual comments on, and approved the final manuscript.

Corresponding authors

Correspondence to Hasan Mahmud Reza or Mohammad Safiqul Islam.

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Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest

Mohammad Mamun Ur Rashid, Imtiaz Ahmed, Md. Asraful Islam, Tasnova Tasnim, Noor Ahmed Nahid, Mohd Nazmul Hasan Apu, Mir Md. Abdullah Al-Mamun, Md. Reazul Islam, Maizbha Uddin Ahmed, Masud Karim, Md. Nazrul Islam, Kazushige Yokota, Samia Shabnaz, Hasan Mahmud Reza, Mohammad Safiqul Islam, and Abul Hasnat have declared that they have no conflicts of interest.

Ethical approval

The study was conducted in accordance with the Helsinki Declaration and its further amendments, and the ethical committee of the participating hospital approved the study protocol.

Informed consent

Each patient and control subject signed an informed consent document after they were informed of the study objectives.

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Rashid, M.M.U., Ahmed, I., Islam, M.A. et al. Influence of TPMT polymorphisms on azathioprine-induced myelosuppression in Bangladeshi patients with systemic lupus erythematosus. Drugs Ther Perspect 36, 202–207 (2020). https://doi.org/10.1007/s40267-020-00716-y

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  • DOI: https://doi.org/10.1007/s40267-020-00716-y

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