Abstract
Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the meta-analysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR=1.05 (95% confidence interval (CI) 0.83–1.32) and OR=0.81 (95% CI 0.53–1.24), respectively; toxicity: OR=1.38 (95% CI 0.90–2.12) and OR=1.19 (95% CI 0.80–1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985; 312: 818–822.
Williams HJ, Willkens RF, Samuelson Jr CO, Alarcon GS, Guttadauria M, Yarboro C et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 1985; 28: 721–730.
Le Loet X, Berthelot JM, Cantagrel A, Combe B, De Bandt M, Fautrel B et al. Clinical practice decision tree for the choice of the first disease modifying antirheumatic drug for very early rheumatoid arthritis: a 2004 proposal of the French Society of Rheumatology. Ann Rheum Dis 2006; 65: 45–50.
Sokka T, Kautiainen H, Toloza S, Makinen H, Verstappen SM, Lund Hetland M et al. QUEST-RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries. Ann Rheum Dis 2007; 66: 1491–1496.
Alarcon GS, Tracy IC, Blackburn Jr WD . Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 1989; 32: 671–676.
Gispen JG, Alarcon GS, Johnson JJ, Acton RT, Barger BO, Koopman WJ . Toxicity of methotrexate in rheumatoid arthritis. J Rheumatol 1987; 14: 74–79.
Salliot C, van der Heijde D . Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009; 68: 1100–1104.
Hoekstra M, van Ede AE, Haagsma CJ, van de Laar MA, Huizinga TW, Kruijsen MW et al. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis 2003; 62: 423–426.
Anderson JJ, Wells G, Verhoeven AC, Felson DT . Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000; 43: 22–29.
Hider SL, Silman AJ, Thomson W, Lunt M, Bunn D, Symmons DP . Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? Ann Rheum Dis 2009; 68: 57–62.
van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2001; 44: 1515–1524.
Finckh A, Liang MH, van Herckenrode CM, de Pablo P . Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis. Arthritis Rheum 2006; 55: 864–872.
Gubner R, August S, Ginsberg V . Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951; 221: 176–182.
Goyette P, Pai A, Milos R, Frosst P, Tran P, Chen Z et al. Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome 1998; 9: 652–656.
Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 1994; 7: 195–200.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.
van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 1998; 62: 1044–1051.
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. Pharmacogenetics 2002; 12: 183–190.
van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA et al. 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 2001; 44: 2525–2530.
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 Genomics 2007; 17: 383–390.
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: 607–612.
Kim SK, Jun JB, El-Sohemy A, Bae SC . Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 2006; 33: 1266–1274.
Aggarwal P, Naik S, Mishra KP, 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: 521–526.
Bohanec Grabar P, Logar D, Lestan B, Dolzan 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: 1057–1068.
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: 1227–1231.
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: 787–789.
Kumagai K, Hiyama K, Oyama T, Maeda H, Kohno N . 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 2003; 11: 593–600.
Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol 2008; 35: 572–579.
Zeng QY, Wang YK, Xiao ZY, Chen SB . Pharmacogenetic study of 5,10-methylenetetrahydrofolate reductase C677T and thymidylate synthase 3R/2R gene polymorphisms and methotrexate-related toxicity in Chinese Han patients with inflammatory arthritis. Ann Rheum Dis 2008; 67: 1193–1194.
Hughes LB, Beasley TM, Patel H, Tiwari HK, Morgan SL, Baggott JE et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis 2006; 65: 1213–1218.
Dervieux T, Greenstein N, Kremer J . Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum 2006; 54: 3095–3103.
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: 1087–1095.
Kurzawski M, Pawlik A, Safranow K, Herczynska M, Drozdzik M . 677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics 2007; 8: 1551–1559.
Hider SL, Thomson W, Mack LF, Armstrong DJ, Shadforth M, Bruce IN . Polymorphisms within the adenosine receptor 2a gene are associated with adverse events in RA patients treated with MTX. Rheumatology (Oxford) 2008; 47: 1156–1159.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (Oxford, England) 2005; 21: 263–265.
Fisher MC, Cronstein BN . Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 2009; 36: 539–545.
Lee YH, Song GG . Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Clin Drug Investig 2010; 30: 101–108.
DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.
Mantel N, Haenszel W . Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719–748.
Ioannidis JP, Trikalinos TA . The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. Cmaj 2007; 176: 1091–1096.
Breslow NE, Day NE . Statistical methods in cancer research. Volume I—the analysis of case-control studies. IARC Sci Publ 1980: 5–338.
Higgins JP, Thompson SG . Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558.
Zintzaras E, Lau J . Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol 2008; 61: 634–645.
Munafo MR, Flint J . Meta-analysis of genetic association studies. Trends Genet 2004; 20: 439–444.
Lee YC, Cui J, Costenbader KH, Shadick NA, Weinblatt ME, Karlson EW . Investigation of candidate polymorphisms and disease activity in rheumatoid arthritis patients on methotrexate. Rheumatology (Oxford) 2009; 48: 613–617.
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 2009; 27: 499–502.
Fukino K, Kawashima T, Suzuki M, Ueno K . Methylenetetrahydrofolate reductase and reduced folate carrier-1 genotypes and methotrexate serum concentrations in patients with rheumatoid arthritis. J Toxicol Sci 2007; 32: 449–452.
Haagsma CJ, Blom HJ, van Riel PL, van′t Hof MA, Giesendorf BA, van Oppenraaij-Emmerzaal D et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 1999; 58: 79–84.
Hayashi H, Fujimaki C, Daimon T, Tsuboi S, Matsuyama T, Itoh K . Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. J Clin Pharm Ther 2009; 34: 355–361.
Inoue S, Hashiguchi M, Takagi K, Kawai S, Mochizuki M . Preliminary study to identify the predictive factors for the response to methotrexate therapy in patients with rheumatoid arthritis. Yakugaku Zasshi 2009; 129: 843–849.
James HM, Gillis D, Hissaria P, Lester S, Somogyi AA, Cleland LG et al. Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis. J Rheumatol 2008; 35: 562–571.
Milic VD, Damjanov NS, Lukovic LF, Jekic BB, Radunovic GL, Srejic LV et al. Correlation of methotrexate efficacy and toxicity with C677T polymorphism of the methylenetetrahydrofolate reductase in patients with rheumatoid arthritis. Ann Rheum Dis 2008; 67(Suppl II): 441.
Stamp LK, Chapman PT, O′Donnell JL, Zhang M, James J, Frampton C et al. Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate. Pharmacogenet Genomics 2010; 20: 367–376.
Mena JP, Salazar-Paramo M, Gonzalez-Lopez L, Gamez-Nava JI, Sandoval-Ramirez L, Sanchez JD et al. Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases. Pharmacogenomics J 2011; 11: 287–291.
Nishio K, Goto Y, Kondo T, Ito S, Ishida Y, Kawai S et al. Serum folate and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism adjusted for folate intake. J Epidemiol 2008; 18: 125–131.
Oi S . Current status of prenatal management of fetal spina bifida in the world: worldwide cooperative survey on the medico-ethical issue. Childs Nerv Syst 2003; 19: 596–599.
Watanabe H, Fukuoka H, Sugiyama T, Nagai Y, Ogasawara K, Yoshiike N . Dietary folate intake during pregnancy and birth weight in Japan. Eur J Nutr 2008; 47: 341–347.
Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 5: 262–270.
Engbersen AM, Franken DG, Boers GH, Stevens EM, Trijbels FJ, Blom HJ . Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 1995; 56: 142–150.
Harmon DL, Woodside JV, Yarnell JW, McMaster D, Young IS, McCrum EE et al. The common ′thermolabile′ variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. Qjm 1996; 89: 571–577.
Rozen R . Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost 1997; 78: 523–526.
Bagley PJ, Selhub J . A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci USA 1998; 95: 13217–13220.
Weisberg I, Tran P, Christensen B, Sibani S, Rozen R . A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998; 64: 169–172.
Acknowledgements
We thank Arthritis Research UK for their support, Arthritis Research UK grant reference no. 17552; ML, JB, SLH, INB, AB and WT were funded by Arthritis Research UK and SAO's salary was funded by Pfizer. We acknowledge the NIHR Manchester Biomedical Research Centre for their support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Owen, S., Lunt, M., Bowes, J. et al. MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms. Pharmacogenomics J 13, 137–147 (2013). https://doi.org/10.1038/tpj.2011.42
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2011.42
Keywords
This article is cited by
-
MTHFR gene polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis based on 16 studies
Clinical Rheumatology (2020)
-
Associations between the C677T and A1298C polymorphisms of MTHFR and the toxicity of methotrexate in childhood malignancies: a meta-analysis
The Pharmacogenomics Journal (2018)
-
Clinical connection between rheumatoid arthritis and liver damage
Rheumatology International (2018)
-
Nonassociation of homocysteine gene polymorphisms with treatment outcome in South Indian Tamil Rheumatoid Arthritis patients
Clinical and Experimental Medicine (2018)
-
Polymorphisms and Pharmacogenomics for the Clinical Efficacy of Methotrexate in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis
Scientific Reports (2017)