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Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis

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Abstract

The aim of this study was to explore whether the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) play a role in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). MEDLINE and EMBASE database searches and subsequent manual searches were utilized to identify articles in which C677T and A1298C MTHFR polymorphisms were evaluated in RA patients taking MTX. A meta-analysis was conducted to identify associations between MTHFR polymorphisms and MTX toxicity. Twelve studies comprising a total of 2,288 RA patients were included in our meta-analysis. Meta-analysis revealed an association between the overall toxicity of MTX and the MTHFR 677TT genotype (odds ratio [OR] = 1.615, 95 % confidence interval [CI] = 1.185–2.200, p = 0.002). Stratification by ethnicity indicated an association between the MTHFR 677TT genotype and the overall toxicity of MTX in East Asians (OR = 1.583, 95 % CI = 1.075–2.331, p = 0.020). The toxicity of MTX also was found to be associated with the TT genotype in patients taking folate (OR = 1.893, 95 % CI = 1.283–2.793, p = 0.001). Stratification by toxicity type indicated an association between the MTHFR 677TT genotype and any adverse effects (OR = 1.716, 95 % CI = 1.127–2.612, p = 0.012). Meta-analysis stratified by toxicity type indicated an association between the MTHFR 1298CC genotype and any adverse effects (OR = 0.501, 95 % CI = 0.284–0.886, p = 0.017). The results of our meta-analysis suggest that the MTHFR C677T and A1298C polymorphisms are associated with MTX toxicity in RA patients.

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References

  1. Felson DT, Anderson JJ, Meenan RF (1990) The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 33(10):1449–1461

    Article  CAS  PubMed  Google Scholar 

  2. Kremer JM (2004) Toward a better understanding of methotrexate. Arthritis Rheum 50(5):1370–1382. doi:10.1002/art.20278

    Article  CAS  PubMed  Google Scholar 

  3. Aletaha D, Smolen JS (2002) The rheumatoid arthritis patient in the clinic: comparing more than 1,300 consecutive DMARD courses. Rheumatology 41(12):1367–1374

    Article  CAS  PubMed  Google Scholar 

  4. Grosflam J, Weinblatt ME (1991) Methotrexate: mechanism of action, pharmacokinetics, clinical indications, and toxicity. Curr Opin Rheumatol 3(3):363–368

    Article  CAS  PubMed  Google Scholar 

  5. Goyette P, Pai A, Milos R, Frosst P, Tran P, Chen Z, Chan M, Rozen R (1998) Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome 9(8):652–656

    Article  CAS  PubMed  Google Scholar 

  6. Rosenberg N, Murata M, Ikeda Y, Opare-Sem O, Zivelin A, Geffen E, Seligsohn U (2002) The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. Am J Hum Genet 70(3):758–762. doi:10.1086/338932

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62(5):1044–1051. doi:10.1086/301825

    Article  PubMed Central  PubMed  Google Scholar 

  8. Caliz R, del Amo J, Balsa A, Blanco F, Silva L, Sanmarti R, Martinez FG, Collado MD, Ramirez Mdel C, Tejedor D, Artieda M, Pascual-Salcedo D, Oreiro N, Andreu JL, Graell E, Simon L, Martinez A, Mulero J (2012) The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol 41(1):10–14. doi:10.3109/03009742.2011.617312

    Article  CAS  PubMed  Google Scholar 

  9. Choe JY, Lee H, Jung HY, Park SH, Bae SC, Kim SK (2012) Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis. Rheumatol Int 32(6):1837–1842. doi:10.1007/s00296-011-1989-5

    Article  CAS  PubMed  Google Scholar 

  10. Xiao H, Xu J, Zhou X, Stankovich J, Pan F, Zhang Z, Xu S, Lian L, Ding C (2010) Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol 28(5):728–733

    CAS  PubMed  Google Scholar 

  11. Mena JP, Salazar-Paramo M, Gonzalez-Lopez L, Gamez-Nava JI, Sandoval-Ramirez L, Sanchez JD, Figuera LE, Munoz-Valle FJ, Vazquez del Mercado M, Davalos IP (2011) Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases. Pharmacogenomics J 11(4):287–291. doi:10.1038/tpj.2010.32

    Article  CAS  PubMed  Google Scholar 

  12. Aggarwal P, Naik S, Mishra KP, Aggarwal A, Misra R (2006) Correlation between methotrexate efficacy and toxicity with C677T polymorphism of the methylenetetrahydrofolate gene in rheumatoid arthritis patients on folate supplementation. Indian J Med Res 124(5):521–526

    CAS  PubMed  Google Scholar 

  13. Kim SK, Jun JB, El-Sohemy A, Bae SC (2006) Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 33(7):1266–1274

    CAS  PubMed  Google Scholar 

  14. Wessels JA, Kooloos WM, De Jonge R, De Vries-Bouwstra JK, Allaart CF, Linssen A, Collee G, De Sonnaville P, Lindemans J, Huizinga TW, Guchelaar HJ (2006) Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 54(9):2830–2839. doi:10.1002/art.22032

    Article  CAS  PubMed  Google Scholar 

  15. Kumagai K, Hiyama K, Oyama T, Maeda H, Kohno N (2003) Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int J Mol Med 11(5):593–600

    CAS  PubMed  Google Scholar 

  16. Bohanec Grabar P, Logar D, Lestan B, Dolzan V (2008) Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism. Eur J Clin Pharmacol 64(11):1057–1068. doi:10.1007/s00228-008-0521-7

    Article  CAS  PubMed  Google Scholar 

  17. Taniguchi A, Urano W, Tanaka E, Furihata S, Kamitsuji S, Inoue E, Yamanaka M, Yamanaka H, Kamatani N (2007) 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 17(6):383–390. doi:10.1097/01.fpc.0000236326.80809.b1

    Article  CAS  Google Scholar 

  18. Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, Abou Atta I, Mevorach D, Friedman G, Ben-Yehuda A (2004) Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis 63(10):1227–1231. doi:10.1136/ard.2003.016337

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, de Boo TM, van de Putte LB (2001) The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 44(11):2525–2530

    Article  PubMed  Google Scholar 

  20. Choi SJ, Rho YH, Ji JD, Song GG, Lee YH (2006) Genome scan meta-analysis of rheumatoid arthritis. Rheumatology 45(2):166–170. doi:10.1093/rheumatology/kei128

    Article  CAS  PubMed  Google Scholar 

  21. Lee YH, Ji JD, Song GG (2007) Tumor necrosis factor-alpha promoter -308 A/G polymorphism and rheumatoid arthritis susceptibility: a metaanalysis. J Rheumatol 34(1):43–49

    CAS  PubMed  Google Scholar 

  22. Nath SK, Harley JB, Lee YH (2005) Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis. Hum Genet 118(2):225–234. doi:10.1007/s00439-005-0044-6

    Article  CAS  PubMed  Google Scholar 

  23. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62(10):1006–1012. doi:10.1016/j.jclinepi.2009.06.005

    Article  PubMed  Google Scholar 

  24. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. doi:10.1002/sim.1186

    Article  PubMed  Google Scholar 

  26. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  27. Lee YH, Song GG (2010) Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Clin Drug Invest 30(2):101–108. doi:10.2165/11531070-000000000-00000

    Article  CAS  Google Scholar 

  28. Schneider JA, Rees DC, Liu YT, Clegg JB (1998) Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet 62(5):1258–1260. doi:10.1086/301836

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Yang L, Hu X, Xu L (2012) Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumour Biol 33(5):1445–1454. doi:10.1007/s13277-012-0395-2

    Article  CAS  PubMed  Google Scholar 

  30. Spyridopoulou KP, Dimou NL, Hamodrakas SJ, Bagos PG (2012) Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity: a meta-analysis. Pharmacogenet Genom 22(2):117–133. doi:10.1097/FPC.0b013e32834ded2a

    Article  CAS  Google Scholar 

  31. Huang L, Tissing WJ, de Jonge R, van Zelst BD, Pieters R (2008) Polymorphisms in folate-related genes: association with side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia. Leukemia 22(9):1798–1800. doi:10.1038/leu.2008.66

    Article  CAS  PubMed  Google Scholar 

  32. Ongaro A, De Mattei M, Della Porta MG, Rigolin G, Ambrosio C, Di Raimondo F, Pellati A, Masieri FF, Caruso A, Catozzi L, Gemmati D (2009) Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival. Haematologica 94(10):1391–1398. doi:10.3324/haematol.2009.008326

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Salas M, Hofman A, Stricker BH (1999) Confounding by indication: an example of variation in the use of epidemiologic terminology. Am J Epidemiol 149(11):981–983

    Article  CAS  PubMed  Google Scholar 

  34. van Ede AE, Laan RF, Blom HJ, De Abreu RA, van de Putte LB (1998) Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Semin Arthritis Rheum 27(5):277–292

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported by a grant from the Korean Healthcare Technology R&D Project, Korean Ministry of Health and Welfare (HI12C1834).

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea

    Gwan Gyu Song & Young Ho Lee

  2. Division of Rheumatology, Department of Internal Medicine, Hospital for Rheumatic Diseases, Hanyang University Medical Center, Seoul, South Korea

    Sang-Cheol Bae

  3. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-15-ga, Anam-dong, Seongbuk-gu, Seoul, 136-705, South Korea

    Young Ho Lee

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  1. Gwan Gyu Song
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Correspondence to Young Ho Lee.

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Song, G.G., Bae, SC. & Lee, Y.H. Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. Clin Rheumatol 33, 1715–1724 (2014). https://doi.org/10.1007/s10067-014-2645-8

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  • DOI: https://doi.org/10.1007/s10067-014-2645-8

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