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The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients

  • Original Article - Genes and Disease
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Abstract

Some single-nucleotide polymorphisms (SNPs) might be predictive of methotrexate (MTX) therapeutic outcome in rheumatoid arthritis (RA). The aim of this study was to determine whether SNPs in the methylenetetrahydrofolate reductase (MTHFR) gene are predictive of MTX response. Comparison was made using EULAR response criteria and according to the change of DAS28 (∆DAS28) after a 6-month MTX treatment in RA patient cohort. The two SNPs C677T (rs1801133) and A1298C (rs1801131) have been genotyped. A total of 120 patients were enrolled in the study, and all of them fulfilled the American College of Rheumatology 1987 RA criteria and are currently or previously taking MTX oral treatment, either as a monotherapy (n = 65) or in a combination with other disease-modifying antirheumatic drugs (n = 55). Genotyping was performed using qPCR allelic discrimination. We did not found any association of C677T and A1298C genotypes with MTX treatment inefficacy in dominant model (OR 1.23, 95 % CI 0.57–2.65, P = 0.697; and OR 0.98, 95 % CI 0.47–2.14, P = 1.0, respectively), or in recessive and codominant models. However, when ∆DAS28 after a 6-month therapy was used as a measure of treatment efficacy, the 677CT and 1298AC genotypes were found to be significantly associated with less favorable response to MTX (P = 0.025 and P = 0.043, respectively). In addition, even lower ∆DAS28 was determined for double-mutated 677CT–1298AC heterozygotes. It means that a synergistic effect of 677CT and 1298AC genotypes was observed. Nevertheless, the DAS28 baseline was lower here comparing to other genotypes. Unexpectedly, quite the opposite trend—i.e., better response to MTX—was found in genotypes 677CC–1298CC and 677TT–1298AA. It is an intriguing finding, because these double-mutated homozygotes are known for their low MTHFR-specific activity. Global significance was P = 0.013, η 2 = 0.160—i.e., large-size effect. Thus, our data show greater ability of 677CC–1298CC and 677TT–1298AA genotypes to respond to MTX treatment.

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Acknowledgments

This study has been funded by MH CZ - DRO (UHHK, 00179906) to T. S.

Conflict of interest

None of the authors have financial interests that could create a potential competing interest or the appearance of a conflict of interest with regard to the work.

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Authors and Affiliations

  1. Faculty of Medicine and University Hospital, 2nd Department of Internal Medicine - Gastroenterology, Charles University in Prague, Sokolska 581, 500 05, Hradec Kralove, Czech Republic

    Tomas Soukup & Petr Bradna

  2. Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic

    Martin Dosedel, Ales Antonin Kubena & Jiri Vlcek

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic

    Petr Pavek & Alejandro Fernández Carazo

  4. Institute of Clinical Biochemistry and Diagnostics, University Hospital in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic

    Jana Nekvindova & Iva Bubancova

  5. Faculty of Mathematics and Physics, Institute of Physics, Charles University in Prague, Prague, Czech Republic

    Ivan Barvik

  6. Department of Emergency, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic

    Tomas Veleta

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  1. Tomas Soukup
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Soukup, T., Dosedel, M., Pavek, P. et al. The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients. Rheumatol Int 35, 1149–1161 (2015). https://doi.org/10.1007/s00296-015-3219-z

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