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Polymorphisms of the methylenetetrahydrofolate reductase gene and clinical outcomes in HLA-matched sibling allogeneic hematopoietic stem cell transplantation

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Abstract

To evaluate whether the C677T and A1298C polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) are related to the toxicity of methotrexate (MTX) used in allogeneic stem cell transplantation, we performed association analysis between these genetic polymorphisms and the clinical outcomes of patients treated using human leukocyte antigen-matched sibling stem cell transplantation. Patients (n=72) with hematological malignancy or aplastic anemia were given a short course of MTX as a graft-versus-host disease prophylaxis. Patients with the 677TT genotype showed higher total bilirubin levels (677TT vs 677CT vs 677CC, 14.5 vs 8.6 vs 3.8 mg/dl, respectively; p=0.07) and higher aspartic transaminase levels (677TT vs 677CT vs 677CC, 678.9 vs 156.6 vs 111.8 IU/l; p=0.04). Platelet recovery to 20,000/μl was slower for patients with the 677TT genotype than for patients with other genotypes (677TT, 59 days; 677CT, 26 days; 677CC, 26 days; p=0.0075). The influences of the C677T polymorphism on treatment-related mortality (TRM) were also analyzed. One-year cumulative TRMs for patients with the TT genotype and the other genotypes were 66 and 30% (p=0.04) and their respective 1-year overall survivals were 30 and 56% (p=0.11). No association was observed between the A1298C polymorphism and clinical outcome for any of the different genotypes. Therefore, patients at high risk of developing hepatic toxicity and with a poor likelihood of survival could be selected by genotyping MTHFR C677T before allogeneic stem cell transplantation.

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References

  1. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, Buckner CD, Clift R, Doney K, Farewell V et al (1986) Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 314:729–735

    Article  PubMed  CAS  Google Scholar 

  2. Tishler M, Caspi D, Fishel B, Yaron M (1988) The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 31:906–908

    PubMed  CAS  Google Scholar 

  3. Joyce DA, Will RK, Hoffman DM, Laing B, Blackbourn SJ (1991) Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis 50:913–914

    Article  PubMed  CAS  Google Scholar 

  4. Baggott JE, Vaughn WH, Hudson BB (1986) Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 59-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide. Biochem J 236:193–200

    PubMed  CAS  Google Scholar 

  5. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113

    Article  PubMed  CAS  Google Scholar 

  6. Bagley PJ, Selhub J (1998) 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 95:13217–13220

    Article  PubMed  CAS  Google Scholar 

  7. Shaw GM, Rozen R, Finnell RH, Wasserman CR, Lammer EJ (1998) Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida. Am J Epidemiol 148:30–37

    PubMed  CAS  Google Scholar 

  8. Ou CY, Stevenson RE, Brown VK, Schwartz CE, Allen WP, Khoury MJ, Rozen R, Oakley GP Jr, Adams MJ Jr (1996) 5,10-Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects. Am J Med Genet 63:610–614

    Article  PubMed  CAS  Google Scholar 

  9. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 6:12810–12815

    Article  Google Scholar 

  10. 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 62:1044–1051

    Article  PubMed  Google Scholar 

  11. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED (1974) Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18:295–304

    Article  PubMed  CAS  Google Scholar 

  12. Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, Lerner KG, Glucksberg H, Buckner CD (1975) Bone-marrow transplantation. N Engl J Med 292:895–902

    Article  PubMed  CAS  Google Scholar 

  13. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RA (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 118:255–267

    PubMed  CAS  Google Scholar 

  14. Reeves GK, Cox DR, Darby SC (1998) Some aspects of measurement error in explanatory variables for continuous and binary regression models. Stat Med 17:2157–2177

    Article  PubMed  CAS  Google Scholar 

  15. Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H, Matsuda Y, Akama H, Kitamura Y, Kamatani N (2002) 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 12:183–190

    Article  PubMed  CAS  Google Scholar 

  16. Finkelstein JD (1990) Methionine metabolism in mammals. J Nutr Biochem 1:228–237

    Article  PubMed  CAS  Google Scholar 

  17. 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 44:2525–2530

    Article  PubMed  Google Scholar 

  18. Garcia-Tevijano ER, Berasain C, Rodriguez JA, Corrales FJ, Arias R, Martin-Duce A, Caballeria J, Mato JM, Avila MA (2001) Hyperhomocysteinemia in liver cirrhosis: mechanisms and role in vascular and hepatic fibrosis. Hypertension 38:1217–1221

    PubMed  CAS  Google Scholar 

  19. Robien K, Ulrich CM, Bigler J, Yasui Y, Gooley T, Bruemmer B, Potter JD, Radich JP (2004) Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia. Clin Cancer Res 10:7592–7598

    Article  PubMed  CAS  Google Scholar 

  20. Winkelmayer WC, Kramar R, Sunder-Plassmann G, Fodinger M (2005) Effects of single-nucleotide polymorphisms in MTHFR and MTRR on mortality and allograft loss in kidney transplant recipients. Kidney Int 68:2857–2862

    Article  PubMed  CAS  Google Scholar 

  21. Kalayoglu-Besisik S, Caliskan Y, Sargin D, Gurses N, Ozbek U (2003) Methylenetetrahydrofolate reductase C677T polymorphism and toxicity in allogeneic hematopoietic cell transplantation. Transplantation 76:1775–1777

    Article  PubMed  Google Scholar 

  22. Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, Ariail KS, Keener CL, Li S, Liu H, Farin FM, Potter JD (2001) Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 98:231–234

    Article  PubMed  CAS  Google Scholar 

  23. Murphy N, Diviney M, Szer J, Bardy P, Grigg A, Hoyt R, King B, Macgregor L, Holdsworth R, McCluskey J, Tait BD (2006) Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate. Bone Marrow Transplant 37:773–779

    Article  PubMed  CAS  Google Scholar 

  24. Blount BC, Ames BN (1995) DNA damage in folate deficiency. Baillieres Clin Haematol 8:461–478

    Article  PubMed  CAS  Google Scholar 

  25. Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99:5606–5611

    Article  PubMed  CAS  Google Scholar 

  26. Szczeklik A, Sanak M, Jankowski M, Dropinski J, Czachor R, Musial J, Axenti I, Twardowska M, Brzostek T, Tendera M (2001) Mutation A1298C of Methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia. Am J Med Genet 101:36–39

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

This study was supported by a grant of the Korea Health 21 R & D project, Ministry of Health & Welfare, Republic of Korea. (0405-BC02-0604-0004).

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Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110-744, South Korea

    Inho Kim, Kyung-Hun Lee, Sung-Soo Yoon, Seonyang Park & Byoung Kook Kim

  2. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Jin Hee Kim & Yun-Chul Hong

  3. Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Eun Kyung Ra & Sung Sup Park

  4. Department of Internal Medicine, College of Medicine, Inha University, Incheon, Korea

    Chul Soo Kim

  5. Diagnostic DNA Chip Center, The Ilchun Molecular Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea

    Inho Kim & Seonyang Park

  6. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Inho Kim, Sung-Soo Yoon, Seonyang Park & Byoung Kook Kim

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  1. Inho Kim
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Correspondence to Seonyang Park.

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Kim, I., Lee, KH., Kim, J.H. et al. Polymorphisms of the methylenetetrahydrofolate reductase gene and clinical outcomes in HLA-matched sibling allogeneic hematopoietic stem cell transplantation. Ann Hematol 86, 41–48 (2007). https://doi.org/10.1007/s00277-006-0184-3

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  • DOI: https://doi.org/10.1007/s00277-006-0184-3

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