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A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in breast cancer

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Abstract

The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk has been extensively explored, but their results are conflicting rather than conclusive. To derive a more precise estimation, we carried out not only an updated meta-analysis but also a combined analysis based on all the available studies estimating the association between MTHFR C677T and/or A1298C and breast cancer risk. With respect to C677T polymorphism, the results suggested that 677T allele was associated with significantly elevated breast cancer risk in overall analysis (T vs. C: OR 1.073, 95 % CI 1.028–1.120; TT vs. CC: OR 1.177, 95 % CI 1.072–1.293; TT vs. CC + CT: OR 1.175, 95 % CI 1.073–1.288); Stratifying by ethnicity, significantly increased risk was only found in East Asians (T vs. C: OR 1.150, 95 % CI 1.039–1.273; TT vs. CC: OR 1.441, 95 % CI 1.145–1.814; TT vs. CC + CT: OR 1.413, 95 % CI 1.148–1.739); When stratified by menopausal status, statistically significant association was found for postmenopausal women (CT + TT vs. CC: OR 1.092, 95 % CI 1.011–1.179). In regard to A1298C polymorphism, no significant associations were found between the polymorphism and breast cancer risk. With respect to MTHFR haplotypes, significantly elevated breast cancer risk was associated with 677T-1298C for overall result (OR 1.498, 95 % CI 1.143–1.962) and for Caucasians (OR 2.088, 95 % CI 1.277–3.416) when compared with 677C-1298A; Haplotype 677C-1298C might provide higher protection than 677C-1298A in East Asians (OR 0.840, 95 % CI 0.742–0.949). The combined genotypes for C677T and A1298C produced a significant OR for the 677TT/1298AC relative to 677CC/1298AA in overall population (OR 2.047, 95 % CI 1.275–3.288); When stratified by ethnicity, significant ORs were only found for East Asians (677CC/1298CC vs. 677CC/1298AA: OR 0.686, 95 % CI 0.478–0.985; 677TT/1298AC vs. 677CC/1298AA: OR 2.181, 95 % CI 1.179–4.035). The findings suggest that the MTHFR C677T polymorphism but not A1298C, and some variants on their combined genotypes or haplotypes may be involved with the development of breast cancer.

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References

  1. O’Brien JM (2000) Environmental and heritable factors in the causation of cancer: analyses of cohorts of twins from Sweden, Denmark, and Finland, by P. Lichtenstein, N.V. Holm, P.K. Verkasalo, A. Iliadou, J. Kaprio, M. Koskenvuo, E. Pukkala, A. Skytthe, K. Hemminki. N Engl J Med 343:78–84, 2000. Survey of Ophthalmology 45(2):167–168

  2. Kim YI (1999) Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects. Nutr Rev 57(10):314–321

    CAS  PubMed  Google Scholar 

  3. Stover PJ (2004) Physiology of folate and vitamin B12 in health and disease. Nutr Rev 62(6 Pt 2):S3–S12 discussion S13

    Article  PubMed  Google Scholar 

  4. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113. doi:10.1038/ng0595-111

    Article  CAS  PubMed  Google Scholar 

  5. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA 94(7):3290–3295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. 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 

  7. Zintzaras E (2006) Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a meta-analysis. Clin Genet 69(4):327–336. doi:10.1111/j.1399-0004.2006.00605.x

    Article  CAS  PubMed  Google Scholar 

  8. Qi X, Ma X, Yang X, Fan L, Zhang Y, Zhang F, Chen L, Zhou Y, Jiang J (2010) Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk: a meta-analysis from 41 studies with 16,480 cases and 22,388 controls. Breast Cancer Res Treat 123(2):499–506. doi:10.1007/s10549-010-0773-7

    Article  CAS  PubMed  Google Scholar 

  9. Zhang J, Qiu LX, Wang ZH, Wu XH, Liu XJ, Wang BY, Hu XC (2010) MTHFR C677T polymorphism associated with breast cancer susceptibility: a meta-analysis involving 15,260 cases and 20,411 controls. Breast Cancer Res Treat 123(2):549–555. doi:10.1007/s10549-010-0783-5

    Article  CAS  PubMed  Google Scholar 

  10. Qiu LX, Zhang J, Li WH, Zhang QL, Yu H, Wang BY, Wang LP, Wang JL, Wang HJ, Liu XJ, Luo ZG, Wu XH (2011) Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility. Mol Biol Rep 38(4):2295–2299. doi:10.1007/s11033-010-0361-2

    Article  CAS  PubMed  Google Scholar 

  11. Macis D, Maisonneuve P, Johansson H, Bonanni B, Botteri E, Iodice S, Santillo B, Penco S, Gucciardo G, D’Aiuto G, Rosselli Del Turco M, Amadori M, Costa A, Decensi A (2007) Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat 106(2):263–271. doi:10.1007/s10549-006-9491-6

    Article  CAS  PubMed  Google Scholar 

  12. Lissowska J, Gaudet MM, Brinton LA, Chanock SJ, Peplonska B, Welch R, Zatonski W, Szeszenia-Dabrowska N, Park S, Sherman M, Garcia-Closas M (2007) Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. Int J Cancer 120(12):2696–2703. doi:10.1002/ijc.22604

    Article  CAS  PubMed  Google Scholar 

  13. Weiner AS, Boyarskih UA, Voronina EN, Selezneva IA, Sinkina TV, Lazarev AF, Petrova VD, Filipenko ML (2010) Polymorphic variants of folate metabolizing genes (C677T and A1298C MTHFR and C1420T SHMT1 and G1958A MTHFD) are not associated with the risk of breast cancer in the West Siberian Region of Russia. Mol Biol 44(5):720–727. doi:10.1134/s0026893310050067

    Article  CAS  Google Scholar 

  14. Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V, Baisch C, Vollmert C, Illig T, Bruning T, Ko Y, Brauch H (2005) One-carbon metabolism and breast cancer risk: no association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiol Biomarkers Prev 14(12):3015–3018. doi:10.1158/1055-9965.EPI-05-0592

    Article  CAS  PubMed  Google Scholar 

  15. Papandreou CN, Doxani C, Zdoukopoulos N, Vlachostergios PJ, Hatzidaki E, Bakalos G, Ziogas DC, Koufakis T, Zintzaras E (2012) Evidence of association between methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a candidate-gene association study in a South-eastern European population. DNA Cell Biol 31(2):193–198. doi:10.1089/dna.2011.1292

    Article  CAS  PubMed  Google Scholar 

  16. Mir MM, Dar JA, Dar NA, Dar MS, Salam I, Lone MM, Chowdary NA (2008) Combined impact of polymorphism of folate metabolism genes; glutamate carboxypeptidase, methylene tetrahydrofolate reductase and methionine synthase reductase on breast cancer susceptibility in kashmiri women. International journal of health sciences 2(1):3–14

    PubMed Central  PubMed  Google Scholar 

  17. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989. doi:10.1086/319501

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73(5):1162–1169. doi:10.1086/379378

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Excoffier L, Laval G, Schneider S (2005) Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol Bioinform Online 1:47–50

    PubMed Central  CAS  Google Scholar 

  20. Li Z, Zhang Z, He Z, Tang W, Li T, Zeng Z, He L, Shi Y (2009) A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn). Cell Res 19 (4):519-523. doi:10.1038/cr.2009.33

  21. Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15(2):97–98. doi:10.1038/sj.cr.7290272

    Article  CAS  PubMed  Google Scholar 

  22. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Sharp S (1998) sbe23: meta-analysis regression. Stata Tech Bull 42:16–22

    Google Scholar 

  25. 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  PubMed Central  CAS  PubMed  Google Scholar 

  26. Duval S, Tweedie R (2000) Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56(2):455–463

    Article  CAS  PubMed  Google Scholar 

  27. Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC (1992) Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 327(4):248–254. doi:10.1056/NEJM199207233270406

    Article  CAS  PubMed  Google Scholar 

  28. Whitehead A (1997) A prospectively planned cumulative meta-analysis applied to a series of concurrent clinical trials. Stat Med 16(24):2901–2913

    Article  CAS  PubMed  Google Scholar 

  29. Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG (2003) Genetic associations in large versus small studies: an empirical assessment. Lancet 361(9357):567–571. doi:10.1016/S0140-6736(03)12516-0

    Article  PubMed  Google Scholar 

  30. Bagos PG, Nikolopoulos GK (2009) Generalized least squares for assessing trends in cumulative meta-analysis with applications in genetic epidemiology. J Clin Epidemiol 62(10):1037–1044. doi:10.1016/j.jclinepi.2008.12.008

    Article  PubMed  Google Scholar 

  31. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57:289–300

    Google Scholar 

  32. Lin WY, Chou YC, Wu MH, Huang HB, Jeng YL, Wu CC, Yu CP, Yu JC, You SL, Chu TY, Chen CJ, Sun CA (2004) The MTHFR C677T polymorphism, estrogen exposure and breast cancer risk: a nested case-control study in Taiwan. Anticancer Res 24(6):3863–3868

    CAS  PubMed  Google Scholar 

  33. Langsenlehner T, Renner W, Yazdani-Biuki B, Langsenlehner U (2008) Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat 107(3):459–460. doi:10.1007/s10549-007-9564-1

    Article  CAS  PubMed  Google Scholar 

  34. Gao CM, Kazuo T, Tang JH, Cao HX, Ding JH, Wu JZ, Wang J, Liu YT, Li SP, Su P, Keitaro M, Toshiro T (2009) MTHFR polymorphisms, dietary folate intake and risks to breast cancer. Zhonghua yu fang yi xue za zhi 43(7):576–580 [Chinese journal of preventive medicine]

    CAS  PubMed  Google Scholar 

  35. Li W, Chen S (2009) Association of methylenetetrahydrofolate reductase C677T polymorphism and breast cancer risk. J Prac Med 25(13):2031–2033

    CAS  Google Scholar 

  36. Yuan H, Xu X, Wang Z (2009) The relation between polymorphisms of methylenetetrahydrofolate reductase C677T and the risk of breast cancer. J Mudanjiang Med Univ 30(3):2–4

    Google Scholar 

  37. Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, Teitelbaum SL, Britton JA, Terry MB, Neugut AI, Santella RM (2005) One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res 65(4):1606–1614. doi:10.1158/0008-5472.CAN-04-2630

    Article  CAS  PubMed  Google Scholar 

  38. Ericson UC, Ivarsson MI, Sonestedt E, Gullberg B, Carlson J, Olsson H, Wirfalt E (2009) Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele. Am J Clin Nutr 90(5):1380–1389. doi:10.3945/ajcn.2009.28064

    Article  CAS  PubMed  Google Scholar 

  39. Tao MH, Shields PG, Nie J, Marian C, Ambrosone CB, McCann SE, Platek M, Krishnan SS, Xie B, Edge SB, Winston J, Vito D, Trevisan M, Freudenheim JL (2009) DNA promoter methylation in breast tumors: no association with genetic polymorphisms in MTHFR and MTR. Cancer Epidemiol Biomarkers Prev 18(3):998–1002. doi:10.1158/1055-9965.epi-08-0916

    Article  CAS  PubMed  Google Scholar 

  40. Vainer AS, Boiarskikh UA, Voronina EN, Selezneva IA, Sinkina TV, Lazarev AF, Petrova VD, Filipenko ML (2010) Polymorphic variants of folate metabolizing genes (C677T and A1298C MTHFR, C1420T SHMT1 and G1958A MTHFD) are not associated with the risk of breast cancer in West Siberian Region of Russia. Mol Biol 44(5):816–823

    CAS  Google Scholar 

  41. Mohammad NS, Yedluri R, Addepalli P, Gottumukkala SR, Digumarti RR, Kutala VK (2011) Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer. Mol Cell Biochem 349(1–2):159–167. doi:10.1007/s11010-010-0670-8

    Article  CAS  PubMed  Google Scholar 

  42. Naushad SM, Pavani A, Digumarti RR, Gottumukkala SR, Kutala VK (2011) Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer. Mol Biol Rep 38(8):4893–4901. doi:10.1007/s11033-010-0631-z

    Article  CAS  PubMed  Google Scholar 

  43. de Cássia Carvalho Barbosa R, da Costa DM, Cordeiro DE, Vieira AP, Rabenhorst SH (2012) Interaction of MTHFR C677T and A1298C, and MTR A2756G gene polymorphisms in breast cancer risk in a population in Northeast Brazil. Anticancer Res 32(11):4805–4811

    PubMed  Google Scholar 

  44. Jin Z, Lu Q, Ge D, Zong M, Zhu Q (2009) Effect of the methylenetetrahydrofolate reductase gene C677T polymorphism on C-erbB-2 methylation status and its association with cancer. Mol Med Report 2(2):283–289. doi:10.3892/mmr_00000097

    CAS  Google Scholar 

  45. Campbell IG, Baxter SW, Eccles DM, Choong DY (2002) Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res 4(6):R14

    Article  PubMed Central  PubMed  Google Scholar 

  46. Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, Baird JO, Haites NE, Heys SD, Grubb DA (2002) Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett 181(1):65–71

    Article  CAS  PubMed  Google Scholar 

  47. Ergul E, Sazci A, Utkan Z, Canturk NZ (2003) Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol 24(6):286–290

    Article  CAS  PubMed  Google Scholar 

  48. Langsenlehner U, Krippl P, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Weitzer W, Samonigg H (2003) The common 677C > T gene polymorphism of methylenetetrahydrofolate reductase gene is not associated with breast cancer risk. Breast Cancer Res Treat 81(2):169–172. doi:10.1023/A:1025752420309

    Article  CAS  PubMed  Google Scholar 

  49. Semenza JC, Delfino RJ, Ziogas A, Anton-Culver H (2003) Breast cancer risk and methylenetetrahydrofolate reductase polymorphism. Breast Cancer Res Treat 77(3):217–223

    Article  CAS  PubMed  Google Scholar 

  50. Forsti A, Angelini S, Festa F, Sanyal S, Zhang Z, Grzybowska E, Pamula J, Pekala W, Zientek H, Hemminki K, Kumar R (2004) Single nucleotide polymorphisms in breast cancer. Oncol Rep 11(4):917–922

    PubMed  Google Scholar 

  51. Grieu F, Powell B, Beilby J, Iacopetta B (2004) Methylenetetrahydrofolate reductase and thymidylate synthase polymorphisms are not associated with breast cancer risk or phenotype. Anticancer Res 24(5B):3215–3219

    CAS  PubMed  Google Scholar 

  52. Le Marchand L, Haiman CA, Wilkens LR, Kolonel LN, Henderson BE (2004) MTHFR polymorphisms, diet, HRT, and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 13(12):2071–2077

    PubMed  Google Scholar 

  53. Lee SA, Kang D, Nishio H, Lee MJ, Kim DH, Han W, Yoo KY, Ahn SH, Choe KJ, Hirvonen A, Noh DY (2004) Methylenetetrahydrofolate reductase polymorphism, diet, and breast cancer in Korean women. Exp Mol Med 36(2):116–121

    Article  CAS  PubMed  Google Scholar 

  54. Qi J, Miao XP, Tan W, Yu CY, Liang G, Lu WF, Lin DX (2004) Association between genetic polymorphisms in methylenetetrahydrofolate reductase and risk of breast cancer. Zhonghua Zhong Liu Za Zhi 26(5):287–289

    CAS  PubMed  Google Scholar 

  55. Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hebert JR, Jin F, Zheng W (2004) MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai breast cancer study. Cancer Epidemiol Biomarkers Prev 13(2):190–196

    Article  CAS  PubMed  Google Scholar 

  56. Deligezer U, Akisik EE, Dalay N (2005) Homozygosity at the C677T of the MTHFR gene is associated with increased breast cancer risk in the Turkish population. Vivo 19(5):889–893

    CAS  Google Scholar 

  57. Kalemi TG, Lambropoulos AF, Gueorguiev M, Chrisafi S, Papazisis KT, Kotsis A (2005) The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece. Cancer Lett 222(1):57–65. doi:10.1016/j.canlet.2004.11.025

    Article  CAS  PubMed  Google Scholar 

  58. Chou YC, Wu MH, Yu JC, Lee MS, Yang T, Shih HL, Wu TY, Sun CA (2006) Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan. Carcinogenesis 27(11):2295–2300. doi:10.1093/carcin/bgl108

    Article  CAS  PubMed  Google Scholar 

  59. Kalyankumar Ch JK (2006) Methylene tetrahydofolate reductase (MTHFR) C677T and A1298C polymorphisms and breast cancer in South Indian population. Int J Cancer Res 2:143–151

    Article  Google Scholar 

  60. Hekim N, Ergen A, Yaylim I, Yilmaz H, Zeybek U, Ozturk O, Isbir T (2007) No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem Funct 25(1):115–117. doi:10.1002/cbf.1274

    Article  CAS  PubMed  Google Scholar 

  61. Jakubowska A, Gronwald J, Menkiszak J, Gorski B, Huzarski T, Byrski T, Edler L, Lubinski J, Scott RJ, Hamann U (2007) Methylenetetrahydrofolate reductase polymorphisms modify BRCA1-associated breast and ovarian cancer risks. Breast Cancer Res Treat 104(3):299–308. doi:10.1007/s10549-006-9417-3

    Article  CAS  PubMed  Google Scholar 

  62. Kan X, Zou T, Wu X, Wang X (2007) Association betweenmTHFR genotype polymorphism and breast cancer susceptibility in human population from Yunnan. Cancer Res Prev Treat 34(9):716–718

    CAS  Google Scholar 

  63. Reljic A, Simundic AM, Topic E, Nikolac N, Justinic D, Stefanovic M (2007) The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: the Croatian case-control study. Clin Biochem 40(13–14):981–985. doi:10.1016/j.clinbiochem.2007.05.005

    Article  CAS  PubMed  Google Scholar 

  64. Stevens VL, McCullough ML, Pavluck AL, Talbot JT, Feigelson HS, Thun MJ, Calle EE (2007) Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence. Cancer Epidemiol Biomarkers Prev 16(6):1140–1147. doi:10.1158/1055-9965.epi-06-1037

    Article  CAS  PubMed  Google Scholar 

  65. Xu X, Gammon MD, Zhang H, Wetmur JG, Rao M, Teitelbaum SL, Britton JA, Neugut AI, Santella RM, Chen J (2007) Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study. Carcinogenesis 28(7):1504–1509. doi:10.1093/carcin/bgm061

    Article  CAS  PubMed  Google Scholar 

  66. Yu CP, Wu MH, Chou YC, Yang T, You SL, Chen CJ, Sun CA (2007) Breast cancer risk associated with multigenotypic polymorphisms in folate-metabolizing genes: a nested case-control study in Taiwan. Anticancer Res 27(3B):1727–1732

    CAS  PubMed  Google Scholar 

  67. Cheng CW, Yu JC, Huang CS, Shieh JC, Fu YP, Wang HW, Wu PE, Shen CY (2008) Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan. Breast Cancer Res Treat 111(1):145–155. doi:10.1007/s10549-007-9754-x

    Article  CAS  PubMed  Google Scholar 

  68. Inoue M, Robien K, Wang R, Van Den Berg DJ, Koh WP, Yu MC (2008) Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese health study. Carcinogenesis 29(10):1967–1972. doi:10.1093/carcin/bgn177

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Kotsopoulos J, Zhang WW, Zhang S, McCready D, Trudeau M, Zhang P, Sun P, Narod SA (2008) Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat 112(3):585–593. doi:10.1007/s10549-008-9895-6

    Article  CAS  PubMed  Google Scholar 

  70. Suzuki T, Matsuo K, Hirose K, Hiraki A, Kawase T, Watanabe M, Yamashita T, Iwata H, Tajima K (2008) One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 29(2):356–362. doi:10.1093/carcin/bgm295

    Article  CAS  PubMed  Google Scholar 

  71. Cam R, Eroglu A, Egin Y, Akar N (2009) Dihydrofolate reductase (DHRF) 19-bp intron-1 deletion and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms in breast cancer. Breast Cancer Res Treat 115(2):431–432. doi:10.1007/s10549-008-0054-x

    Article  PubMed  Google Scholar 

  72. Ericson U, Sonestedt E, Ivarsson MI, Gullberg B, Carlson J, Olsson H, Wirfalt E (2009) Folate intake, methylenetetrahydrofolate reductase polymorphisms, and breast cancer risk in women from the Malmo Diet and Cancer cohort. Cancer Epidemiol Biomarkers Prev 18(4):1101–1110. doi:10.1158/1055-9965.EPI-08-0401

    Article  CAS  PubMed  Google Scholar 

  73. Gao CM, Tang JH, Cao HX, Ding JH, Wu JZ, Wang J, Liu YT, Li SP, Su P, Matsuo K, Takezaki T, Tajima K (2009) MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women. J Hum Genet 54(7):414–418. doi:10.1038/jhg.2009.57

    Article  CAS  PubMed  Google Scholar 

  74. Henriquez-Hernandez LA, Murias-Rosales A, Hernandez Gonzalez A, Cabrera De Leon A, Diaz-Chico BN, Mori De Santiago M, Fernandez Perez L (2009) Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: a case-control study. Oncol Rep 22(6):1425–1433

    Article  CAS  PubMed  Google Scholar 

  75. Jakubowska A, Jaworska K, Cybulski C, Janicka A, Szymanska-Pasternak J, Lener M, Narod SA, Lubinski J, Group IH-BCS (2009) Do BRCA1 modifiers also affect the risk of breast cancer in non-carriers? Eur J Cancer 45(5):837–842. doi:10.1016/j.ejca.2008.10.021

    Article  CAS  PubMed  Google Scholar 

  76. Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, Motola J Jr, Laginha FM, Tsugane S (2009) Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer 9:122. doi:10.1186/1471-2407-9-122

    Article  PubMed Central  PubMed  Google Scholar 

  77. Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S (2009) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan. Nutr Cancer 61(4):447–456. doi:10.1080/01635580802610123

    Article  CAS  PubMed  Google Scholar 

  78. Maruti SS, Ulrich CM, Jupe ER, White E (2009) MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case-control study. Breast Cancer Res 11(6):R91. doi:10.1186/bcr2462

    Article  PubMed Central  PubMed  Google Scholar 

  79. Platek ME, Shields PG, Marian C, McCann SE, Bonner MR, Nie J, Ambrosone CB, Millen AE, Ochs-Balcom HM, Quick SK, Trevisan M, Russell M, Nochajski TH, Edge SB, Freudenheim JL (2009) Alcohol consumption and genetic variation in methylenetetrahydrofolate reductase and 5-methyltetrahydrofolate-homocysteine methyltransferase in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev 18(9):2453–2459. doi:10.1158/1055-9965.epi-09-0159

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Alshatwi AA (2010) Breast cancer risk, dietary intake, and methylenetetrahydrofolate reductase (MTHFR)single nucleotide polymorphisms. Food Chem Toxicol 48(7):1881–1885. doi:10.1016/j.fct.2010.04.028

    Article  CAS  PubMed  Google Scholar 

  81. Bentley AR, Raiszadeh F, Stover PJ, Hunter DJ, Hankinson SE, Cassano PA (2010) No association between cSHMT genotypes and the risk of breast cancer in the Nurses’ Health Study. Eur J Clin Nutr 64(1):108–110. doi:10.1038/ejcn.2009.104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Lin J, Chen S, Li W (2010) Single nucleotide polymorphisms in methylenetetrahydrofolate reductase gene and susceptibility to breast cancer. Mod Hosp 10(3):15–17

    Google Scholar 

  83. Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T, Yoshida T (2010) Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case-control study in Thai women. Breast Cancer Res Treat 123(3):885–893. doi:10.1007/s10549-010-0804-4

    Article  CAS  PubMed  Google Scholar 

  84. Wu Y, Yuan X, Zheng H, Chu Y, Zhang J (2010) Association between genetic polymorphisms of MTHFR C677T and susceptibility to breast cancer on population from Northeast China. Mod Oncol 18(12):2375–2378

    CAS  Google Scholar 

  85. Batschauer AP, Cruz NG, Oliveira VC, Coelho FF, Santos IR, Alves MT, Fernandes AP, Carvalho MG, Gomes KB (2011) HFE, MTHFR, and FGFR4 genes polymorphisms and breast cancer in Brazilian women. Mol Cell Biochem 357(1–2):247–253. doi:10.1007/s11010-011-0895-1

    Article  CAS  PubMed  Google Scholar 

  86. Han H, Han LL, Gao HD, Hou L (2011) Genetic polymorphisms of methylenetetrahydrofolate reductase, methionine synthase, methylation of NF2, and their association with breast cancer mobidity. Chin J Curr Adv Gen Surg 14(11):846–850

    CAS  Google Scholar 

  87. Hosseini M, Houshmand M, Ebrahimi A (2011) MTHFR polymorphisms and breast cancer risk. Arch Med Sci 7(1):134–137. doi:10.5114/aoms.2011.20618

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Hua ZP, Wang YB, Ni J, Ge F, Zou TN (2011) Folic acid, Vitam in B12, MTHFR, MS gene polymorphisms associate with the risk of breast cancer. Mod Oncol 19(3):428–431

    CAS  Google Scholar 

  89. Prasad VV, Wilkhoo H (2011) Association of the functional polymorphism C677T in the methylenetetrahydrofolate reductase gene with colorectal, thyroid, breast, ovarian, and cervical cancers. Onkologie 34(8–9):422–426. doi:10.1159/000331131

    Article  CAS  PubMed  Google Scholar 

  90. Ziva Cerne J, Stegel V, Gersak K, Novakovic S (2011) Lack of association between methylenetetrahydrofolate reductase genetic polymorphisms and postmenopausal breast cancer risk. Mol Med Report 4(1):175–179. doi:10.3892/mmr.2010.406

    Google Scholar 

  91. Akram M, Malik FA, Kayani MA (2012) Mutational analysis of the MTHFR gene in breast cancer patients of Pakistani population. Asian Pac J Cancer Prev 13(4):1599–1603

    Article  PubMed  Google Scholar 

  92. Carvalho Barbosa Rde C, Menezes DC, Freire TF, Sales DC, Alencar VH, Rabenhorst SH (2012) Associations of polymorphisms of folate cycle enzymes and risk of breast cancer in a Brazilian population are age dependent. Mol Biol Rep 39(4):4899–4907. doi:10.1007/s11033-011-1285-1

    Article  PubMed  Google Scholar 

  93. Diakite B, Tazzite A, Hamzi K, Jouhadi H, Nadifi S (2012) Methylenetetrahydrofolate Reductase C677T polymorphism and breast cancer risk in Moroccan women. Afr Health Sci 12(2):204–209. doi:10.4314/ahs.v12i2.20

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Lajin B, Alhaj Sakur A, Ghabreau L, Alachkar A (2012) Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women. Tumour Biol 33(4):1133–1139. doi:10.1007/s13277-012-0354-y

    Article  CAS  PubMed  Google Scholar 

  95. Naushad SM, Pavani A, Rupasree Y, Divyya S, Deepti S, Digumarti RR, Gottumukkala SR, Prayaga A, Kutala VK (2012) Association of aberrations in one-carbon metabolism with molecular phenotype and grade of breast cancer. Mol Carcinog 51(Suppl 1):E32–E41. doi:10.1002/mc.21830

    Article  CAS  PubMed  Google Scholar 

  96. Wu XY, Ni J, Xu WJ, Zhou T, Wang X (2012) Interactions between MTHFR C677T-A1298C variants and folic acid deficiency affect breast cancer risk in a Chinese population. Asian Pac J Cancer Prev 13(5):2199–2206

    Article  PubMed  Google Scholar 

  97. Wu Y, Wu L, Wang Y, Cao W, Hou L (2012) Relation between the SNPs in Methylenetetrahydrofolate Reductase Gene C677T and G1793A and the Susceptibility of Sporadic Breast Cancer. Prog Mod Biomed 12(14):2606–2609

    Google Scholar 

  98. Ames BN (1999) Cancer prevention and diet: help from single nucleotide polymorphisms. Proc Natl Acad Sci USA 96(22):12216–12218

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Zintzaras E, Lau J (2008) Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol 61(7):634–645. doi:10.1016/j.jclinepi.2007.12.011

    Article  PubMed  Google Scholar 

  100. Zintzaras E (2010) Genetic variants of homocysteine/folate metabolism pathway and risk of inflammatory bowel disease: a synopsis and meta-analysis of genetic association studies. Biomarkers 15(1):69–79. doi:10.3109/13547500903297184

    Article  CAS  PubMed  Google Scholar 

  101. Zintzaras E, Koufakis T, Ziakas PD, Rodopoulou P, Giannouli S, Voulgarelis M (2006) A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia. Eur J Epidemiol 21(7):501–510. doi:10.1007/s10654-006-9027-8

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (81272470).

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Authors and Affiliations

  1. Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China

    Shanliang Zhong & Jianhua Zhao

  2. Department of General Surgery, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, China

    Zhiyuan Chen

  3. Department of Hematology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China

    Xinnian Yu

  4. Department of Clinical Laboratory, Suzhou Municipal Hospital (Headquarters), Suzhou, 215002, China

    Wenjing Li

  5. Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, 210009, China

    Jinhai Tang

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  1. Shanliang Zhong
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  2. Zhiyuan Chen
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  3. Xinnian Yu
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  4. Wenjing Li
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Correspondence to Jianhua Zhao.

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Shanliang Zhong and Zhiyuan Chen have Contributed equally to this article.

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Zhong, S., Chen, Z., Yu, X. et al. A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in breast cancer. Mol Biol Rep 41, 5775–5785 (2014). https://doi.org/10.1007/s11033-014-3450-9

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