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Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs).

Methods

The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX.

Results

According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed.

Conclusion

The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.

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Acknowledgments

This work was supported by the Serbian Ministry of Education and Science [grant 175091].

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000, Belgrade, Serbia

    Biljana Jekic, Ljiljana Lukovic, Vera Bunjevacki, Ivana Novakovic, Tatjana Damnjanovic & Nela Maksimovic

  2. Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000, Belgrade, Serbia

    Vera Milic, Nemanja Damjanov, Goran Radunovic & Ljiljana Kovacevic

  3. Institute of Biology and Human Genetics, Faculty of Dentistry, University of Belgrade, 1 Dr Subotica Str, 11000, Belgrade, Serbia

    Jelena Milasin & Branka Popovic

  4. Centre de Recherche, CHU Sainte-Justine, Departments of Pediatrics and Pharmacology, University of Montréal, 3175 Chemin de la Côte-Ste-Catherine, Montreal, QC, H3T 1C5, Canada

    Maja Krajinovic

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  1. Biljana Jekic
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  2. Ljiljana Lukovic
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Correspondence to Biljana Jekic.

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Jekic, B., Lukovic, L., Bunjevacki, V. et al. Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients. Eur J Clin Pharmacol 69, 377–383 (2013). https://doi.org/10.1007/s00228-012-1341-3

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  • DOI: https://doi.org/10.1007/s00228-012-1341-3

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