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Influence of dihydrofolate reductase gene polymorphisms rs408626 (-317A>G) and rs442767 (-680C>A) on the outcome of methotrexate-based maintenance therapy in South Indian patients with acute lymphoblastic leukemia

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

The most common cause of treatment failure in acute lymphoblastic leukaemia (ALL) is the relapse. Genetic polymorphisms of dihydrofolate reductase (DHFR) enzyme affect the response to methotrexate (MTX) treatment. Inter-individual variability exists in the distribution of DHFR variants, and they influence MTX treatment outcome. To the best of our knowledge, there are no genetic studies reported from India, which have explored the influence of DHFR variants on the outcome of MTX treatment. Therefore, we aim to study the influence of DHFR rs408626 (-317A>G) and rs442767 (-680C>A) variants on ALL outcome in South Indian patients.

Methods

A total of 70 ALL patients who were on MTX-based maintenance therapy were recruited for the study. DNA was extracted from leukocytes, and genotyping was done by real-time PCR.

Results

The DHFR-317GG genotype was associated with the increased risk of relapse in patients with ALL (relative risk 2.25, 95 % confidence interval (CI) 1.38 to 3.6, p = 0.02). DHFR-317AA and -680CA genotypes were found to be associated with severe leucopenia (p < 0.05). In Cox regression model, -317GG genotype was found to have lower relapse-free survival (hazard ratio (HR) 2.56, 95 % CI 1.06 to 6.19, p = 0.03) and overall survival (HR 3.72, 95 % CI 1.44 to 9.65, p = 0.007). Similarly, patients with white blood cell (WBC) count >50,000 cells/mm3 were also found to have lower relapse-free survival (HR 2.20, 95 % CI 1.10 to 4.79, p = 0.04) and overall survival (HR 3.30, 95 % CI 1.45 to 7.53, p = 0.004).

Conclusion

The GG genotype of DHFR-317A>G variant is associated with increased risk of ALL relapse and lower overall survival in South Indian population. Both variants of DHFR (-317 AA and -680 CA) are found to be associated with severe leucopenia caused by MTX.

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Acknowledgments

We thank the Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India, for providing intramural fund to conduct the study. We also thank Mr. Ravi Prasad for assisting us in the laboratory work.

Conflict of interest

The authors declare that they have no competing interests.

Compliance with Ethical Standards

All procedures performed in the present study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. The study was supported by an intramural grant from JIPMER.

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Authors and Affiliations

  1. Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Gorimedu, Puducherry, India

    Sunitha Kodidela & Suresh Chandra Pradhan

  2. Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Gorimedu, Puducherry, India

    Biswajit Dubashi

  3. Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Gorimedu, Puducherry, India

    Debdatta Basu

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  1. Sunitha Kodidela
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Correspondence to Sunitha Kodidela.

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Kodidela, S., Pradhan, S.C., Dubashi, B. et al. Influence of dihydrofolate reductase gene polymorphisms rs408626 (-317A>G) and rs442767 (-680C>A) on the outcome of methotrexate-based maintenance therapy in South Indian patients with acute lymphoblastic leukemia. Eur J Clin Pharmacol 71, 1349–1358 (2015). https://doi.org/10.1007/s00228-015-1930-z

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