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Association of hyperhomocysteinemia with genetic variants in key enzymes of homocysteine metabolism and methotrexate toxicity in rheumatoid arthritis patients

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Abstract

Objectives

The study investigated the association between plasma homocysteine, folate and vitamin B12 with 5,10 methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TYMS 2R → 3R) and methionine synthase (MTR A2756G) polymorphisms and methotrexate (MTX) treatment and toxicity in Tunisian Rheumatoid arthritis (RA) patients.

Methods

A total of 185 patients with RA were included. Homocysteine (Hcy) was assessed by fluorescence polarization immunoassay, and folate and vitamin B12 were measured by chemiluminescence immunoassays. The genetic polymorphisms were analyzed by PCR or PCR-RFLP. Hyperhomocysteinemia (HHC) was considered for Hcy > 15 µmol/L.

Results

MTHFR C677T polymorphism was associated with HHC in RA patients (multi-adjusted OR, 95% CI 2.18, [1.07–4.57]; p = 0.031). No association was detected with the remaining polymorphisms. Plasma Hcy, folate, and vitamin B12 did not differ according to each polymorphism, or with MTX treatment or toxicity. However, HHC was more prevalent in patients with than those without MTX toxicity (32.7 vs. 16.7%; p = 0.035).

Conclusions

The MTHFR 677TT genotype is an independent risk factor for HHC in Tunisians RA patients. HHC could be a useful marker of MTX toxicity in RA patients.

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Acknowledgements

We thank the patients for their cooperation. This work was supported by the Ministry of Higher Education and Scientific Research and the Ministry of Health, Tunisia. This paper is dedicated to the memory of Pr Abdellatif Maalej who passed away on august 2017.

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Authors and Affiliations

  1. Laboratory of Human Molecular Genetics, Faculty of Medicine, Avenue Majida Boulila, 3029, Sfax, Tunisia

    Souhir Chaabane, Mariem Ben Hamad, Leila Keskes & Abdellatif Maalej

  2. UR “Molecular Bases of Human Diseases”, Faculty of Medicine, Sfax, Tunisia

    Meriam Messedi, Mouna Turki & Fatma Ayedi

  3. Department of Rheumatology, University Hospital Hedi Chaker, Sfax, Tunisia

    Rim Akrout

  4. Department of Internal Medicine, University Hospital Hedi Chaker, Sfax, Tunisia

    Sameh Marzouk & Zouheir Bahloul

  5. Laboratory of Molecular and Cellular Screening Processes, Center of Biotechnology, Sfax, Tunisia

    Ahmed Rebai

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  1. Souhir Chaabane
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Correspondence to Souhir Chaabane.

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All procedures performed in studies 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. For this type of study, formal consent is not required.

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Responsible Editor: John Di Battista.

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Chaabane, S., Messedi, M., Akrout, R. et al. Association of hyperhomocysteinemia with genetic variants in key enzymes of homocysteine metabolism and methotrexate toxicity in rheumatoid arthritis patients. Inflamm. Res. 67, 703–710 (2018). https://doi.org/10.1007/s00011-018-1161-8

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  • DOI: https://doi.org/10.1007/s00011-018-1161-8

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