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Associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with genetic susceptibility to rheumatoid arthritis: a meta-analysis

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Abstract

The aim of our study was to conduct a meta-analysis to assess whether combined evidence shows associations between C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and genetic susceptibility to rheumatoid arthritis (RA). A total of 11 articles involving 20 comparisons were included, containing 12 comparisons for the MTHFR C677T polymorphism and 8 comparisons for the MTHFR A1298C polymorphism. Significant evidence was detected for the association of RA susceptibility with the MTHFR C677T polymorphism T allele under allelic contrast and dominant model in Asians (T versus C, OR = 1.300, 95 % CI = 1.104–1.531, p = 0.002; TT + CT versus CC, OR = 1.495, 95 % CI = 1.187–1.882, p = 0.001). Significant association between RA susceptibility and the MTHFR A1298C polymorphism A allele under recessive model was found in the overall meta-analysis (AA versus AC + CC, OR = 1.281, 95 % CI = 1.048–1.565, p = 0.016). Our meta-analysis results demonstrate that the MTHFR C677T polymorphism is involved in the genetic susceptibility of RA in Asians, and the MTHFR A1298C polymorphism is associated with genetic susceptibility to RA in the overall population. Given the paucity of studies, especially in non-Asian populations, further studies with larger sample sizes are required to elucidate the role of MTHFR polymorphisms in the genetic basis of RA in different ethnic populations.

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References

  1. Scott DL, Wolfe F, Huizinga TW (2010) Rheumatoid arthritis. Lancet 376:1094–1108

    Article  PubMed  Google Scholar 

  2. Li R, Sun J, Ren LM, Wang HY, Liu WH, Zhang XW, Chen S, Mu R, He J, Zhao Y, Long L, Liu YY, Liu X, Lu XL, Li YH, Wang SY, Pan SS, Li C, Wang HY, Li ZG (2012) Epidemiology of eight common rheumatic diseases in China: a large-scale cross-sectional survey in Beijing. Rheumatology (Oxford) 51:721–729

    Article  Google Scholar 

  3. Viatte S, Plant D, Raychaudhuri S (2013) Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 9:141–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rosenblatt DS (2001) Methylenetetrahydrofolate reductase. Clin Invest Med 24:56–59

    CAS  PubMed  Google Scholar 

  5. Klein K, Gay S (2015) Epigenetics in rheumatoid arthritis. Curr Opin Rheumatol 27:76–82

    Article  CAS  PubMed  Google Scholar 

  6. Lazzerini PE, Selvi E, Lorenzini S, Capecchi PL, Ghittoni R, Bisogno S, Catenaccio M, Marcolongo R, Galeazzi M, Laghi-Pasini F (2006) Homocysteine enhances cytokine production in cultured synoviocytes from rheumatoid arthritis patients. Clin Exp Rheumatol 24:387–393

    CAS  PubMed  Google Scholar 

  7. Fujimaki C, Hayashi H, Tsuboi S, Matsuyama T, Kosuge K, Yamada H, Inoue K, Itoh K (2009) Plasma total homocysteine level and methylenetetrahydrofolate reductase 677C>T genetic polymorphism in Japanese patients with rheumatoid arthritis. Biomarkers 14:49–54

    Article  CAS  PubMed  Google Scholar 

  8. 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 9:652–656

    Article  CAS  PubMed  Google Scholar 

  9. Cornélis F, Fauré S, Martinez M, Prud’homme JF, Fritz P, Dib C, Alves H, Barrera P, de Vries N, Balsa A, Pascual-Salcedo D, Maenaut K, Westhovens R, Migliorini P, Tran TH, Delaye A, Prince N, Lefevre C, Thomas G, Poirier M, Soubigou S, Alibert O, Lasbleiz S, Fouix S, Bouchier C, Lioté F, Loste MN, Lepage V, Charron D, Gyapay G, Lopes-Vaz A, Kuntz D, Bardin T, Weissenbach J, ECRAF (1998) New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc Natl Acad Sci U S A 95:10746–10750

    Article  PubMed  PubMed Central  Google Scholar 

  10. Shiozawa S, Hayashi S, Tsukamoto Y, Goko H, Kawasaki H, Wada T, Shimizu K, Yasuda N, Kamatani N, Takasugi K, Tanaka Y, Shiozawa K, Imura S (1998) Identification of the gene loci that predispose to rheumatoid arthritis. Int Immunol 10:1891–1895

    Article  CAS  PubMed  Google Scholar 

  11. MacKay K, Eyre S, Myerscough A, Milicic A, Barton A, Laval S, Barrett J, Lee D, White S, John S, Brown MA, Bell J, Silman A, Ollier W, Wordsworth P, Worthington J (2002) Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. Arthritis Rheum 46:632–639

    Article  CAS  PubMed  Google Scholar 

  12. Lee, YH, Bae, SC (2015) Association between susceptibility to rheumatoid arthritis and PADI4 polymorphisms: a meta-analysis. Clin Rheumatol [Epub ahead of print]

  13. Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G (1988) Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43:414–421

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Rozen R (1997) Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost 78:523–526

    CAS  PubMed  Google Scholar 

  15. van der Put NM, Gabreëls 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 62:1044–1051

    Article  PubMed  PubMed Central  Google Scholar 

  16. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64:169–172

    Article  CAS  PubMed  Google Scholar 

  17. Friedman G, Goldschmidt N, Friedlander Y, Ben-Yehuda A, Selhub J, Babaey S, Mendel M, Kidron M, Bar-On H (1999) A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr 129:1656–1661

    CAS  PubMed  Google Scholar 

  18. Boughrara W, Aberkane M, Fodil M, Benzaoui A, Dorgham S, Zemani F, Dahmani C, Petit-Teixeira E, Boudjema A (2015) Impact of MTHFR rs1801133, MTHFR rs1801131 and ABCB1 rs1045642 polymorphisms with increased susceptibility of rheumatoid arthritis in the West Algerian population: a case-control study. Acta Reumatol Port 40:363–371

    CAS  PubMed  Google Scholar 

  19. Saad MN, Mabrouk MS, Eldeib AM, Shaker OG (2015) Genetic case-control study for eight polymorphisms associated with rheumatoid arthritis. PLoS One 10(7):e0131960

    Article  PubMed  PubMed Central  Google Scholar 

  20. Soukup T, Dosedel M, Pavek P, Nekvindova J, Barvik I, Bubancova I, Bradna P, Kubena AA, Carazo AF, Veleta T, Vlcek J (2015) The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients. Rheumatol Int 35:1149–1161

    Article  CAS  PubMed  Google Scholar 

  21. Saleh MM, Irshaid YM, Mustafa KN (2015) Methylene tetrahydrofolate reductase genotypes frequencies: association with toxicity and response to methotrexate in rheumatoid arthritis patients. Int J Clin Pharmacol Ther 53:154–162

    Article  PubMed  Google Scholar 

  22. Inanir A, Yigit S, Tekcan A, Tural S, Kismali G (2013) IL-4 and MTHFR gene polymorphism in rheumatoid arthritis and their effects. Immunol Lett 152:104–108

    Article  CAS  PubMed  Google Scholar 

  23. Shi YH, Zhou RH, Xu J, Zhu FX, Li BZ, Li LM, Mo HY (2013) Relationship between single nucleotide polymorphism of methylenetetrahydrofolate reductase gene and the side effect of low-dose methotrexate in the treatment of rheumatoid arthritis. Chin J New Clin Med 6:211–214

    Google Scholar 

  24. Plaza-Plaza JC, Aguilera M, Cañadas-Garre M, Chemello C, González-Utrilla A, Faus Dader MJ, Calleja MA (2012) Pharmacogenetic polymorphisms contributing to toxicity induced by methotrexate in the southern Spanish population with rheumatoid arthritis. OMICS 16:589–595

    Article  CAS  PubMed  Google Scholar 

  25. Taşbaş O, Borman P, Gürhan Karabulut H, Tükün A, Yorgancıoğlu R (2011) The frequency of A1298C and C677T polymorphisms of the methylenetetrahydrofolate gene in Turkish patients with rheumatoid arthritis: relationship with methotrexate toxicity. Open Rheumatol J 5:30–35

    Article  PubMed  PubMed Central  Google Scholar 

  26. Xiao H, Xu JH, Zhou XM, Zhang ZH, Shen SH, Li YW (2011) Correlation of methylene tetrahydrofolate reductase gene single nucleotide polymorphisms and therapeutic effect of methotrexate in rheumatoid arthritis patients. Acta Univ Med Anhui 46:1157–1161

    CAS  Google Scholar 

  27. Palomino-Morales R, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Rodriguez L, Miranda-Filloy JA, Fernandez-Gutierrez B, Llorca J, Martin J, Gonzalez-Gay MA (2010) A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis. Arthritis Res Ther 12:R71

    Article  PubMed  PubMed Central  Google Scholar 

  28. Cai YM, Gong WX (2009) Linkage study on methylenetetrahydrofolate reductase single nucleotide polymorphisms and methotrexate-related adverse effects in patients with rheumatoid arthritis. Chin J Prim Med Pharm 16:1155–1157

    CAS  Google Scholar 

  29. Taraborelli M, Andreoli L, Archetti S, Ferrari M, Cattaneo R, Tincani A (2009) 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 27:499–502

    CAS  PubMed  Google Scholar 

  30. Rubini M, Padovan M, Baricordi O, Fotinidi M, Govoni M, Trotta F (2008) The c.1298A>C polymorphism in the methylenetetrahydrofolate reductase gene is associated with rheumatoid arthritis susceptibility in Italian patients. Clin Exp Rheumatol 26:163

    CAS  PubMed  Google Scholar 

  31. Ghodke Y, Chopra A, Joshi K, Patwardhan B (2008) Are thymidylate synthase and methylene tetrahydrofolate reductase genes linked with methotrexate response (efficacy, toxicity) in Indian (Asian) rheumatoid arthritis patients? Clin Rheumatol 27:787–789

    Article  PubMed  Google Scholar 

  32. Zhou XM, Xu JH, Xu SQ (2008) Relationship between the single nucleotide polymorphism of 5,10-methylenetetrahydrofolate reductase gene and the treatment of methotrexate in rheumatoid arthritis. Chin J Rheumatol 12:598–602

    CAS  Google Scholar 

  33. Xu XY, Wang MM, Xiao CS (2007) The study of the relationship of MTHFR polymorphisms with rheumatoid diseases. J Southeast Univ (Med Sci Edi) 26:38–41

    Google Scholar 

  34. Hughes LB, Beasley TM, Patel H, Tiwari HK, Morgan SL, Baggott JE, Saag KG, McNicholl J, Moreland LW, Alarcón GS, Bridges SL Jr (2006) 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 65:1213–1218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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 63:1227–1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Egger M, Smith GD, Phillips AN (1997) Meta-analysis: principles and procedures. BMJ 315:1533–1537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097

    Article  PubMed  PubMed Central  Google Scholar 

  38. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Article  CAS  PubMed  Google Scholar 

  42. Favalli EG, Biggioggero M, Meroni PL (2014) Methotrexate for the treatment of rheumatoid arthritis in the biologic era: still an “anchor” drug? Autoimmun Rev 13:1102–1108

    Article  CAS  PubMed  Google Scholar 

  43. Song GG, Bae SC, Lee YH (2014) Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. Clin Rheumatol 33:1715–1724

    Article  PubMed  Google Scholar 

  44. Morgan MD, Al-Shaarawy N, Martin S, Robinson JI, Twigg S, YEAR Consortium, Magdy AA, Omar AS, Ghattas MH, Emery P, Barrett JH, Morgan AW (2014) MTHFR functional genetic variation and methotrexate treatment response in rheumatoid arthritis: a meta-analysis. Pharmacogenomics 15:467–475

    Article  CAS  PubMed  Google Scholar 

  45. Lopez-Olivo MA, Gonzalez-Lopez L, Garcia-Gonzalez A, Villa-Manzano AI, Cota-Sanchez AR, Salazar-Paramo M, Varon-Villalpando E, Cardona-Muñoz EG, Gamez-Nava JI (2006) Factors associated with hyperhomocysteinaemia in Mexican patients with rheumatoid arthritis. Scand J Rheumatol 35:112–116

    Article  CAS  PubMed  Google Scholar 

  46. Armstrong DJ, Quinn AD, McCausland EM, Finch MB, Wright GD (2007) Relationship between homocysteine and body mass index in rheumatoid arthritis. Scand J Rheumatol 36:243

    Article  CAS  PubMed  Google Scholar 

  47. Woolf K, Manore MM (2008) Elevated plasma homocysteine and low vitamin B-6 status in nonsupplementing older women with rheumatoid arthritis. J Am Diet Assoc 108:443–453

    Article  CAS  PubMed  Google Scholar 

  48. Davis LA, Cannon GW, Pointer LF, Haverhals LM, Wolff RK, Mikuls TR, Reimold AM, Kerr GS, Richards JS, Johnson DS, Valuck R, Prochazka A, Caplan L (2013) Cardiovascular events are not associated with MTHFR polymorphisms, but are associated with methotrexate use and traditional risk factors in US veterans with rheumatoid arthritis. J Rheumatol 40:809–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Brambila-Tapia AJ, Durán-González J, Sandoval-Ramírez L, Mena JP, Salazar-Páramo M, Gámez-Nava JI, González-López L, Lazalde-Medina BB, Dávalos NO, Peralta-Leal V, Vázquez del Mercado M, Beltrán-Miranda CP, Dávalos IP (2012) MTHFR C677T, MTHFR A1298C, and OPG A163G polymorphisms in Mexican patients with rheumatoid arthritis and osteoporosis. Dis Markers 32:109–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Saad MN, Mabrouk MS, Eldeib AM, Shaker OG (2015) Effect of MTHFR, TGFβ1, and TNFB polymorphisms on osteoporosis in rheumatoid arthritis patients. Gene 568:124–128

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Zhejiang Provincial Key Laboratory of Pathophysiology, Nature Science Foundation of Ningbo city (Grant No. 2015A610205), Ningbo University Talent Project (F01256144702), School Research Foundation of Ningbo University (XKL14D2094, XKL14D2095), and K.C. Wong Magna Fund from Ningbo University.

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  1. Department of Preventive Medicine, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People’s Republic of China

    Han Cen, Li-Na Zhang, Li-Ya Liu & Ren-Jie Zhuo

  2. Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People’s Republic of China

    Han Cen, Li-Na Zhang, Li-Ya Liu & Ren-Jie Zhuo

  3. Department of Rheumatology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59 Liuting Road, Ningbo, Zhejiang, 315010, People’s Republic of China

    Hua Huang, Li Zhou & Xia-Fei Xin

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  1. Han Cen
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Han Cen and Hua Huang contributed equally to this work and should be considered as co-first author.

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Cen, H., Huang, H., Zhang, LN. et al. Associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with genetic susceptibility to rheumatoid arthritis: a meta-analysis. Clin Rheumatol 36, 287–297 (2017). https://doi.org/10.1007/s10067-016-3348-0

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