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No correlation between MTHFR c.677 C > T, MTHFR c.1298 A > C, and ABCB1 c.3435 C > T polymorphisms and methotrexate therapeutic outcome of rheumatoid arthritis in West Algerian population

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Inflammation Research Aims and scope Submit manuscript

Abstract

Context

The c.677 C > T and c.1298 A > C polymorphisms of methylenetatrahydrofolate reductase (MTHFR) gene and c.3435 C > T polymorphism of ATP-Binding cassette B1 (ABCB1) gene are reported as pharmacogenetic markers, influencing the methotrexate (MTX) therapeutic outcome in rheumatoid arthritis (RA) patients.

Objectives

The aims of this study were to determine the relationship between these polymorphisms and clinical response and/or adverse drug reaction (ADRs) to MTX treatment.

Materials and methods

The cohort of our study was composed of 110 RA patients of the West Algerian population. The clinical response was evaluated using the disease activity score 28 (DAS28) and the ADRs were collected after physical examination of patients. All samples were genotyped for theses polymorphisms by TaqMan® allelic discrimination assay.

Results

Based on EULAR criteria, 59.09% RA patients were responders and ADRs were observed in 40.9% patients. The frequency distribution of these three polymorphisms was similar between the responders and the non-responders. The same result was found on ADRs study and no significant difference of distribution between the presence of ADRs group and absence of ADRs group was observed.

Discussion

Our study joins the results that found in others population in the world.

Conclusion

We have demonstrated, for the first time in the West Algerian population, that these polymorphisms were not predictive for clinical response and/or ADRs to MTX therapeutic outcome.

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References

  1. Cunha VRd, Brenol CV, Brenol JCT, Xavier RM. Rheumatoid arthritis and metabolic syndrome. Revista brasileira de reumatologia. 2011;51(3):264–8.

    Article  Google Scholar 

  2. Rego-Pérez I, Fernández-Moreno M, Blanco FJ. Gene polymorphisms and pharmacogenetics in rheumatoid arthritis. Curr Genom. 2008;9(6):381–93. doi:10.2174/138920208785699553.

    Article  Google Scholar 

  3. Rozen R. Annotation Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis. 1996;19(5):589–94.

    Article  CAS  PubMed  Google Scholar 

  4. Leclerc D, Rozen R. Génétique moléculaire de MTHFR: Les polymorphismes ne sont pas tous bénins. MS Méd Sci. 2007;23(3):297–302.

    Google Scholar 

  5. Stamp L, Roberts R, Kennedy M, Barclay M, O’Donnell J, Chapman P. The use of low dose methotrexate in rheumatoid arthritis—are we entering a new era of therapeutic drug monitoring and pharmacogenomics? Biomed Pharmacother. 2006;60(10):678–87.

    Article  CAS  PubMed  Google Scholar 

  6. Song GG, Bae S-C, Lee YH. Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. Clin Rheumatol. 2014;33(12):1715–24.

    Article  PubMed  Google Scholar 

  7. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochimica et Biophysica Acta (BBA)-Biomembranes. 1976;455(1):152–62.

    Article  CAS  Google Scholar 

  8. Hoffmeyer S, Burk O, Von Richter O, Arnold H, Brockmöller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci. 2000;97(7):3473–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen J, Chen L, Mao N, Liu Y. Association of the MDR1 3435 polymorphism in patients with refractory rheumatoid arthritis in a Chinese population. Rheumatol Int. 2012;32(10):3127–30. doi:10.1007/s00296-011-2088-3.

    Article  CAS  PubMed  Google Scholar 

  10. Plaza-Plaza JC, Aguilera M, Cañadas-Garre M, Chemello C, González-Utrilla A, Faus Dader MJ, et al. Pharmacogenetic polymorphisms contributing to toxicity induced by methotrexate in the southern Spanish population with rheumatoid arthritis. OMICS. 2012;16(11):589–95.

    Article  CAS  PubMed  Google Scholar 

  11. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.

    Article  CAS  PubMed  Google Scholar 

  12. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd et al. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.

    Article  PubMed  Google Scholar 

  13. Jekic B, Lukovic L, Bunjevacki V, Milic V, Novakovic I, Damnjanovic T, 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. 2013;69(3):377–83.

    Article  CAS  PubMed  Google Scholar 

  14. Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tregouet D, Tiret L. Cox proportional hazards survival regression in haplotype-based association analysis using the Stochastic-EM algorithm. Eur J Hum Genet. 2004;12(11):971–4.

    Article  CAS  PubMed  Google Scholar 

  16. Perdriger A, Rihouey D, Verdier M. Pharmacogénomique et traitement de la polyarthrite rhumatoïde Pharmacogenomics andtreatment of rheumatoid arthritis. Revue du rhumatisme monographies. 2010;77:341–5.

    Article  Google Scholar 

  17. Combe B, Flipo R. Polyarthrite rhumatoïde de l’adulte : traitement de la polyarthrite rhumatoïde de l’adulte. DIU Web Etudes approfondies des polyarthrites et maladies systémiques. 2008;5.

  18. Cush JJ. Early rheumatoid arthritis—is there a window of opportunity? J Rheumatol Suppl. 2007;80:1–7.

    CAS  PubMed  Google Scholar 

  19. Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364:263–9. doi:10.1016/S0140-6736(04)16676-2.

    Article  PubMed  Google Scholar 

  20. Ghodke Y, Chopra A, Joshi K, Patwardhan B. Are Thymidylate synthase and Methylene tetrahydrofolate reductase genes linked with methotrexate response (efficacy, toxicity) in Indian (Asian) rheumatoid arthritis patients? Clin Rheumatol. 2008;27(6):787–9.

    Article  PubMed  Google Scholar 

  21. Taraborelli M, Andreoli L, Archetti S, Ferrari M, Cattaneo R, Tincani A. Methylenetetrahydrofolate reductase polymorphisms and methotrexate: no association with response to therapy nor with drug-related adverse events in an Italian population of rheumatic patients. Clin Exp Rheumatol. 2008;27(3):499–502.

    Google Scholar 

  22. Salazar J, Moya P, Altés A, Díaz-Torné C, Casademont J, Cerdà-Gabaroi D, et al. Polymorphisms in genes involved in the mechanism of action of methotrexate: are they associated with outcome in rheumatoid arthritis patients? Pharmacogenomics. 2014;15(8):1079–90.

    Article  CAS  PubMed  Google Scholar 

  23. Morgan MD, Al-Shaarawy N, Martin S, Robinson JI, Twigg S, Magdy AA, et al. MTHFR functional genetic variation and methotrexate treatment response in rheumatoid arthritis: a meta-analysis. Pharmacogenomics. 2014;15(4):467–75.

    Article  CAS  PubMed  Google Scholar 

  24. Aggarwal P, Naik S, Mishra K, Aggarwal A, Misra R. Correlation between methotrexate efficacy & toxicity with C677T polymorphism of the methylenetetrahydrofolate gene in rheumatoid arthritis patients on folate supplementation. Indian J Med Res. 2006;124(5):521.

    CAS  PubMed  Google Scholar 

  25. Wessels JA, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YP, Allaart CF, et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum. 2006;54(4):1087–95.

    Article  CAS  PubMed  Google Scholar 

  26. Lima A, Monteiro J, Bernardes M, Sousa H, Azevedo R, Seabra V et al. Prediction of methotrexate clinical response in Portuguese rheumatoid arthritis patients: implication of MTHFR rs1801133 and ATIC rs4673993 polymorphisms. BioMed Res Int. 2014;2014.

  27. Weisman MH, Furst DE, Park GS, Kremer JM, Smith KM, Wallace DJ, et al. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum. 2006;54(2):607–12.

    Article  CAS  PubMed  Google Scholar 

  28. Świerkot J, Ślęzak R, Karpiński P, Pawłowska J, Noga L, Szechiński J, et al. Associations between single-nucleotide polymorphisms of RFC-1, GGH, MTHFR, TYMS, and TCII genes and the efficacy and toxicity of methotrexate treatment in patients with rheumatoid arthritis. Pol Arch Med Wewn. 2015;125(3):152–61.

    PubMed  Google Scholar 

  29. Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H, Matsuda Y, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenet Genom. 2002;12(3):183–90.

    Article  CAS  Google Scholar 

  30. Taniguchi A, Urano W, Tanaka E, Furihata S, Kamitsuji S, Inoue E, et al. Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice. Pharmacogenet Genom. 2007;17(6):383–90.

    Article  CAS  Google Scholar 

  31. Saleh MM, Irshaid YM, Mustafa KN. Methylene tetrahydrofolate reductase genotypes frequencies: association with toxicity and response to methotrexate in rheumatoid arthritis patients. Int J Clin Pharmacol Ther. 2015;53(2):154–62.

    Article  PubMed  Google Scholar 

  32. Choe J-Y, Lee H, Jung H-Y, Park S-H, Bae S-C, Kim S-K. Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis. Rheumatol Int. 2012;32(6):1837–42.

    Article  CAS  PubMed  Google Scholar 

  33. Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, et al. Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis. 2004;63(10):1227–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Grabar PB, Logar D, Lestan B, Dolžan V. Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism. Eur J Clin Pharmacol. 2008;64(11):1057–68.

    Article  Google Scholar 

  35. Kooloos WM, Wessels JA, van der Straaten T, Allaart CF, Huizinga TW, Guchelaar H-J. Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis. Pharmacogenomics. 2010;11(2):163–75.

    Article  CAS  PubMed  Google Scholar 

  36. Samara SA, Irshaid YM, Mustafa KN. Association of MDR1 C3435T and RFC1 G80A polymorphisms with methotrexate toxicity and response in Jordanian rheumatoid arthritis patients. Int J Clin Pharmacol Ther. 2014;52(9):746–55.

    Article  CAS  PubMed  Google Scholar 

  37. Takatori R, Takahashi K, Tokunaga D, Hojo T, Fujioka M, Asano T, et al. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin Exp Rheumatol. 2006;24(5):546–54.

    CAS  PubMed  Google Scholar 

  38. Pawlik A, Wrzesniewska J, Fiedorowicz-Fabrycy I, Gawronska-Szklarz B. The MDR1 3435 polymorphism in patients with rheumatoid arthritis. Int J Clin Pharmacol Ther. 2004;42(9):496–503.

    Article  CAS  PubMed  Google Scholar 

  39. Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Aneja R, et al. Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians. Pharmacogenet Genom. 2008;18(12):1041–9.

    Article  CAS  Google Scholar 

  40. Leschziner G, Zabaneh D, Pirmohamed M, Owen A, Rogers J, Coffey AJ, Balding DJ, Bentley DB, Johnson MR. Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance. Pharmacogenet Genom. 2006;16(6):439–50.

    Article  CAS  Google Scholar 

  41. Sai K, Saito Y, Itoda M, Fukushima-Uesaka H, Nishimaki-Mogami T, Ozawa S, et al. Genetic variations and haplotypes of ABCC2 encoding MRP2 in a Japanese population. Drug Metab Pharmacokinet. 2008;23(2):139–47.

    Article  CAS  PubMed  Google Scholar 

  42. Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS, Lee CG. Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic asian populations. Pharmacogenetics. 2002;12(6):437–50.

    Article  CAS  PubMed  Google Scholar 

  43. Halilova KI, Brown EE, Morgan SL, Bridges SL, Hwang M-H, Arnett DK, et al. Markers of treatment response to methotrexate in rheumatoid arthritis: where do we stand? Int J Rheumatol. 2012;2012:978396.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to RA patients, their families, healthy volunteers, and rheumatologists for participation in this study. We thank Pr. Baba Ahmed Bey (Department of Biotechnology, Université d’Oran IGMO), for technical support.

Author information

Authors and Affiliations

  1. Laboratoire de génétique moléculaire et cellulaire, Université des sciences et de la technologie d’Oran Mohamed Boudiaf (USTO-MB), BP 1505, El-M’naouar, 31000, Oran, Algeria

    Wefa Boughrara, Fatima Zohra Moghtit, Samia Dorgham, Aicha sarah Lardjam-Hetraf, Hadjer Ouhaibi-Djellouli & Abdallah Boudjema

  2. Ecole préparatoire en science de la nature et de la vie d’Oran (EPSNVO), Oran, Algeria

    Wefa Boughrara

  3. Service de Rhumatologie, Centre Hospitalo-universitaire d’Oran (CHUO), Université d’Oran 1, Oran, Algeria

    Ahmed Benzaoui

  4. Département de pharmacie, Université d’Oran 1, Oran, Algeria

    Meriem Aberkane

  5. GenHotel-EA3886, Evry-Val d’Essonne University, Evry-Genopole, France

    Elisabeth Petit Teixeira

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  1. Wefa Boughrara
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  2. Ahmed Benzaoui
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Correspondence to Wefa Boughrara.

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Responsible Editor: John Di Battista.

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Boughrara, W., Benzaoui, A., Aberkane, M. et al. No correlation between MTHFR c.677 C > T, MTHFR c.1298 A > C, and ABCB1 c.3435 C > T polymorphisms and methotrexate therapeutic outcome of rheumatoid arthritis in West Algerian population. Inflamm. Res. 66, 505–513 (2017). https://doi.org/10.1007/s00011-017-1034-6

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  • DOI: https://doi.org/10.1007/s00011-017-1034-6

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