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Association between Maternal and Fetal MTHFR C677T and MTRR A66G Polymorphisms with the Risk of NTDs: A Systematic Review and Meta-Analysis Study

Document Type : Review articles

Authors

1 Department of Pediatrics, School of Medicine, Ayatollah Mousavi Hospital, Zanjan University of Medical Sciences, Zanjan, Iran

2 Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran

3 Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

Abstract

Background: Neural tube defects (NTDs) are classed as multifactorial birth defects of the brain and spinal cord that arise during embryonic development. Although the etiology is not well understood, NTDs are reported to be prevented by maternal folic acid supplementation before and during early pregnancy.
Objectives: This meta-analysis study aimed to assess the association between fetal and maternal methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with the risk of NTDs.
Methods: The PubMed, Scopus, and Springer Link databases were searched (from March 2000 to November 2020) for the literature on the association between MTHFR C677T and MTRR A66G polymorphisms with the risk of NTDs.
Results: In total, 33 studies were reviewed in the present study, and it was revealed that, unlike MTRR A66G polymorphism, MTHFR C677T was statistically associated with the risk of NTDs in the overall population. The results of subgroup analysis showed that the Indian subcontinent subgroup with maternal MTHFR C677T polymorphism and the European subgroup with fetal MTHFR C677T polymorphism was significantly susceptible to NTDs.
Conclusion: The obtained results revealed that, unlike MTRR A66G, maternal and fetal MTHFR C677T polymorphisms were significantly associated with NTDs. Subgroup analysis also demonstrated that folic acid deprivation can be considered the main cause of MTHFR C677T polymorphism in some areas.

Keywords

References
  1. Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat. Rev. Genet 2003;4(10):784-93. doi: 10.1038/nrg1181. [PubMed: 13679871].
  2. Ouyang S, Liu Z, Li Y, Ma F, Wu J. Cystathionine beta-synthase 844ins68 polymorphism is unrelated to susceptibility to neural tube defects. Gene. 2014;535(2):119-23. doi: 10.1016/j.gene.2013.11.052. [PubMed: 24316487].
  3. Au KS, Ashley‐Koch A, Northrup H. Epidemiologic and genetic aspects of spina bifida and other neural tube defects. Dev. Disabil. Res. Rev. 2010;16(1):6-15. doi: 10.1002/ddrr.93. [PubMed: 20419766].
  4. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural-tube defects with folic acid in China. N. Engl. 1999;341(20):1485-90. doi: 10.1056/NEJM199911113412001. [PubMed: 10559448].
  5. Gaughan DJ, Kluijtmans LA, Barbaux S, McMaster D, Young IS, Yarnell JW, et al. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis. 2001;157(2):451-6. doi: 10.1016/s0021-9150(00)00739-5. [PubMed: 11472746].
  6. Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. 1992;327(26):1832-5. doi: 10.1056/NEJM199212243272602. [PubMed: 1307234].
  7. Smithells R, Sheppard S, Schorah C, Seller M, Nevin N, Harris R, et al. Possible prevention of neural-tube defects by periconceptional vitamin supplementation. Lancet. 1980;315(8164):339-40. doi: 10.1016/s0140-6736(80)90886-7. [PubMed: 6101792].
  8. Frosst P, Blom H, Milos R, Goyette P, Sheppard CA, Matthews R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 1995;10(1):111-3. doi: 10.1038/ng0595-111. [PubMed: 7647779].
  9. Liew S-C, Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015;58(1):1-10. doi: 10.1016/j.ejmg.2014.10.004. [PubMed: 25449138].
  10. 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(2):195-200. doi: 10.1038/ng0694-195. [PubMed: 7920641].
  11. Rosenberg N, Murata M, Ikeda Y, Opare-Sem O, Zivelin A, Geffen E, et al. The frequent 5, 10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. Am. J. Hum. Genet. 2002;70(3):758-62. doi: 10.1086/338932. [PubMed: 11781870].
  12. Leclerc D, Wilson A, Dumas R, Gafuik C, Song D, Watkins D, et al. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc. Natl. Acad. Sci. U.S.A. 1998;95(6):3059-64. doi: 10.1073/pnas.95.6.3059. [PubMed: 9501215].
  13. Olteanu H, Banerjee R. Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. J. Biol. Chem. 2001;276(38):35558-63. doi: 10.1074/jbc.M103707200. [PubMed: 11466310].
  14. Rai V, Yadav U, Kumar P. MTRR A66G polymorphism among two caste groups of Uttar Pradesh (India). Indian J. Med. Sci. 2012;66(5/6):136. doi: 10.4103/0019-5359.114200. [PubMed: 23806987].
  15. Lucock M, Daskalakis I, Briggs D, Yates Z, Levene M. Altered folate metabolism and disposition in mothers affected by a spina bifida pregnancy: influence of 677c→ t methylenetetrahydrofolate reductase and 2756a→ g methionine synthase genotypes. Mol. Genet. Metab. 2000;70(1):27-44. doi: 10.1006/mgme.2000.2994. [PubMed: 10833329].
  16. Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol. Genet. Metab. 1999;67(4):317-23. doi: 10.1006/mgme.1999.2879. [PubMed: 10444342].
  17. Zhu H, Wicker NJ, Shaw GM, Lammer EJ, Hendricks K, Suarez L, et al. Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects Mol. Genet. Metab. 2003;78(3):216-21. doi: 10.1006/mgme.1999.2879. [PubMed: 10444342].
  18. Lin L, Chu H. Quantifying publication bias in meta‐analysis. Biometrics. 2018;74(3):785-94. doi: 10.1111/biom.12817. [PubMed: 29141096].
  19. Liu J, Qi J, Yu X, Zhu J, Zhang L, Ning Q, et al. Investigations of single nucleotide polymorphisms in folate pathway genes in Chinese families with neural tube defects. J. Neurol. Sci. 2014;337(1-2):61-6. doi: 10.1016/j.jns.2013.11.017. [PubMed: 24326202].
  20. Obeid R, Holzgreve W, Pietrzik K. Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? J Perinat Med. 2013;41(5):469-83. doi: 10.1515/jpm-2012-0256. [PubMed: 23482308].
  21. Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, et al. Thermolabile variant of 5, 10-methylenetetrahydrofolate reductaseassociated with low red-cell folates: implications for folate intake recommendations. Lancet. 1997;349(9065):1591-3. doi: 10.1016/S0140-6736(96)12049-3. [PubMed: 9174561].
  22. Molloy AM, Mills JL, Kirke PN, Ramsbottom D, McPartlin JM, Burke H, et al. Low blood folates in NTD pregnancies are only partly explained by thermolabile 5, 10‐methylenetetrahydrofolate reductase: low folate status alone may be the critical factor. Am. J. Med. Genet. 1998;78(2):155-9. [PubMed: 9674907].
  23. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb. Haemost. 1997;78(01):523-6. [PubMed: 9198208].
  24. Candito M, Rivet R, Herbeth B, Boisson C, Rudigoz RC, Luton D, et al. Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural tube defects: a multicenter case–control study. Am. J. Med. Genet. A . 2008;146(9):1128-33. doi: 10.1002/ajmg.a.32199. [PubMed: 18386810].
  25. Husna M, Endom I, Ibrahim S, Selvi NA, Fakhrurazi H, Htwe RO, et al., editors. Screening of polymorphisms for MTHFR and DHFR genes in spina bifida children and their mothers. AIP Conference Proceedings; 2013: American Institute of Physics.
  26. O’Leary VB, Mills JL, Pangilinan F, Kirke PN, Cox C, Conley M, et al. Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol. Genet. Metab. 2005;85(3):220-7. doi: 10.1016/j.ymgme.2005.02.003. [PubMed: 15979034].
  27. Parle-McDermott A, Mills JL, Kirke PN, O'Leary VB, Swanson DA, Pangilinan F, et al. Analysis of the MTHFR 1298A→ C and 677C→ T polymorphisms as risk factors for neural tube defects. J. Hum. Genet. 2003;48(4):190-3. doi: 10.1007/s10038-003-0008-4. [PubMed: 12730722].
  28. Yang Y, Chen J, Wang B, Ding C, Liu H. Association between MTHFR C677T polymorphism and neural tube defect risks: A comprehensive evaluation in three groups of NTD patients, mothers, and fathers. Birth Defects Res. Part A Clin. Mol. Teratol. 2015;103(6):488-500. doi: 10.1002/bdra.23361. [PubMed: 25808073].
  29. Yadav U, Kumar P, Yadav SK, Mishra OP, Rai V. Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis. Metab. Brain Dis. 2015;30(1):7-24. doi: 10.1007/s11011-014-9575-7. [PubMed: 25005003].
  30. Tabatabaei RS, Fatahi-Meibodi N, Meibodi B, Javaheri A, Abbasi H, Hadadan A, et al. Association of Fetal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects: A Systematic Review and Update Meta-Analysis. Fetal and Pediatric Pathology. 2020:1-17. doi: 10.1080/15513815.2020.1775734. [PubMed: 32536242].
  31. Abbas A, Sifi K, Naimi D, Benmebarek K, Abadi N. Genetic Polymorphisms in Methionine Synthase and Methionine Synthase Reductase, their Metabolic Effects, and Risk of Neural Tube Defects in Algerian Population.
  32. Nasri K, Midani F, Kallel A, Jemaa NB, Aloui M, Boulares M, et al. Association of MTHFR C677T, MTHFR A1298C, and MTRR A66G Polymorphisms with Neural Tube Defects in Tunisian Parents. Pathobiology. 2019;86(4):190-200. doi: 10.1159/000499498. [PubMed: 31238314].
  33. Ouyang S, Liu Z, Li Y, Wu J. Meta-analyses on the association of MTR A2756G and MTRR A66G polymorphisms with neural tube defect risks in Caucasian children. J. Matern.-Fetal Neonatal Med. 2013;26(12):1166-70. doi: 10.3109/14767058.2013.777699. [PubMed: 23425389].
  34. Dávalos I-P, Olivares N, Castillo Ma-T, Cantú J-M, Ibarra B, Sandoval L, et al., editors. The C677T polymorphism of the methylenetetrahydrofolate reductase gene in Mexican mestizo neural-tube defect parents, control mestizo and native populations. Annales de genetique; 2000: Elsevier. doi: 10.1016/s0003-3995(00)90012-1. [PubMed: 10998450].
  35. Lucock M, Daskalakis I, Hinkins M, Yates Z. An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy. Mol. Genet. Metab. 2001;73(4):322-32. doi: 10.1006/mgme.2001.3205. [PubMed: 11509014].
  36. de Villarreal LEMn, Delgado-Enciso I, Valdéz-Leal R, Ortı́z-López R, Rojas-Martı́nez A, Limón-Benavides C, et al. Folate levels and N 5, N 10-methylenetetrahydrofolate reductase genotype (MTHFR) in mothers of offspring with neural tube defects: a case-control study. Arch. Med. Res. 2001;32(4):277-82. doi: 10.1016/s0188-4409(01)00292-2. [PubMed: 11440783].
  37. Garcia-Fragoso L, García-García I, de la Vega A, Renta J, Cadilla CL. Presence of the 5, 10-methylenetetrahydrofolate reductase C677T mutation in Puerto Rican patients with neural tube defects. J. Child Neurol. 2002;17(1):30-2. doi: 10.1177/088307380201700107. [PubMed: 11913566].
  38. Arbour L, Christensen B, Delormier T, Platt R, Gilfix B, Forbes P, et al. Spina bifida, folate metabolism, and dietary folate intake in a Northern Canadian aboriginal population. Int J Circumpolar Health. 2002;61(4):341-51. doi: 10.3402/ijch.v61i4.17492. [PubMed: 12546192].
  39. Perez ABA, D'Almeida V, Vergani N, de Oliveira AC, de Lima FT, Brunoni D. Methylenetetrahydrofolate reductase (MTHFR): incidence of mutations C677T and A1298C in Brazilian population and its correlation with plasma homocysteine levels in spina bifida. Am. J. Med. Genet. 2003;119(1):20-5. doi: 10.1002/ajmg.a.10059. [PubMed: 12707953].
  40. Relton C, Wilding C, Pearce M, Laffling A, Jonas P, Lynch S, et al. Gene–gene interaction in folate-related genes and risk of neural tube defects in a UK population. J. Med. Genet. 2004;41(4):256-60. doi: 10.1136/jmg.2003.010694. [PubMed: 15060097].
  41. Félix TM, Leistner S, Giugliani R. Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil. Birth Defects Res. Part A Clin. Mol. Teratol. 2004;70(7):459-63. doi: 10.1002/bdra.20011. [PubMed: 15259035].
  42. Grandone E, Corrao AM, Colaizzo D, Vecchione G, Girgenti CD, Paladini D, et al. Homocysteine metabolism in families from southern Italy with neural tube defects: role of genetic and nutritional determinants. Prenat. Diag. 2006;26(1):1-5. doi: 10.1002/pd.1359. [PubMed: 16374895].
  43. Dalal A, Pradhan M, Tiwari D, Behari S, Singh U, Mallik G, et al. MTHFR 677C→ T and 1298A→ C polymorphisms: evaluation of maternal genotypic risk and association with level of neural tube defect. Gynecol. Obstet. Invest. 2007;63(3):146-50. doi: 10.1159/000096735. [PubMed: 17085942].
  44. Houcher B, Bourouba R, Djabi F, Yilmaz E, Eğin Y, Akar N. Polymorphisms of 5, 10-Methylenetetrahydrofolate Reductase and Cystathionine β-Synthase Genes as a Risk Factor for Neural Tube Defects in Sétif, Algeria. Pediatr. Neurosurg. 2009;45(6):472-7. doi: 10.1159/000283086. [PubMed: 20160465].
  45. Erdogan M, Yildiz S, Solak M, Eser O, Cosar E, Eser B, et al. C677T polymorphism of the methylenetetrahydrofolate reductase gene does not affect folic acid, vitamin B. Genet. Mol. Res. 2010;9(2):1197-203. doi: 10.4238/vol9-2gmr816. [PubMed: 20589617].
  46. Naushad SM, Devi ARR. Role of parental folate pathway single nucleotide polymorphisms in altering the susceptibility to neural tube defects in South India. J Perinat Med. 2010;38(1):63-9. doi: 10.1515/jpm.2009.119. [PubMed: 20047525].
  47. Godbole K, Gayathri P, Ghule S, Sasirekha BV, Kanitkar‐Damle A, Memane N, et al. Maternal one‐carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India. Birth Defects Res. Part A Clin. Mol. Teratol. 2011;91(9):848-56. doi: 10.1002/bdra.20841. [PubMed: 21770021].
  48. Liu Z-z, Zhang J-t, Dan L, Hao Y-h, Chang B-m, Jun X, et al. Interaction between maternal 5, 10-methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene variants to increase the risk of fetal neural tube defects in a Shanxi Han population. Chin. Med. J. 2013;126(5):865-9. [PubMed: 23489792].
  49. Kondo A, Fukuda H, Matsuo T, Shinozaki K, Okai I. C677T mutation in methylenetetrahydrofolate reductase gene and neural tube defects: Should J apanese women undergo gene screening before pregnancy? Congenit Anom. 2014;54(1):30-4. doi: 10.1111/cga.12026. [PubMed: 24588777].
  50. Wang Y, Liu Y, Ji W, Qin H, Wu H, Xu D, et al. Variants in MTHFR gene and neural tube defects susceptibility in China. Metab. Brain Dis. 2015;30(4):1017-26. doi: 10.1007/s11011-015-9662-4. [PubMed: 25855017].
  51. Bourouba R, Houcher B, Akar N. Risk factors of neural tube defects: A reality of Batna region in Algeria. Egypt. J. Medical Hum. Genet. 2018;19(3):225–9. doi: 10.1016/j.ejmhg.2017.10.003
  52. Nauman N, Jalali S, Shami S, Rafiq S, Große G, Hilger AC, et al. Low maternal folate concentrations and maternal MTHFR C677T polymorphism are associated with an increased risk for neural tube defects in offspring: a case-control study among Pakistani case and control mothers. Asia Pac J Clin Nutr. 2018;27(1):253. doi: 10.6133/apjcn.032017.10. [PubMed: 29222906].
  53. Cai C-Q, Fang Y-L, Shu J-B, Zhao L-S, Zhang R-P, Cao L-R, et al. Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway. Ital. J. Pediatr. 2019;45(1):37. doi: 10.1186/s13052-019-0630-1. [PubMed: 30867013].
  54. Behunova J, Klimcakova L, Zavadilikova E, Potocekova D, Sykora P, Podracka L. Methylenetetrahydrofolate reductase gene polymorphisms and neural tube defects epidemiology in the Slovak population. Birth Defects Res. Part A Clin. Mol. Teratol. 2010;88(8):695-700. doi: 10.1002/bdra.20692. [PubMed: 20672355].
  55. Eser B, Cosar M, Eser O, Erdogan MO, Aslan A, Yildiz H, et al. 677C> T and 1298A> C polymorphisms of methylenetetrahydropholate reductase gene and biochemical parameters in Turkish population with spina bifida occulta. Turk Neurosurg. 2010;20(1):9-15. [PubMed: 20066615].
  56. Fang Y, Zhang R, Zhi X, Zhao L, Cao L, Wang Y, et al. Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China. Childs Nerv Syst. 2018;34(4):725-9. doi: 10.1007/s00381-018-3730-0. [PubMed: 29392422].
  57. Relton CL, Wilding CS, Laffling AJ, Jonas PA, Burgess T, Binks K, et al. Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy. Mol. Genet. Metab. 2004;81(4):273-81. doi: 10.1016/j.ymgme.2003.12.010. [PubMed: 15059614].
  58. Van der Linden IJ, den Heijer M, Afman LA, Gellekink H, Vermeulen SH, Kluijtmans LA, et al. The methionine synthase reductase 66A> G polymorphism is a maternal risk factor for spina bifida. J. Mol. Med. 2006;84(12):1047-54. doi: 10.1007/s00109-006-0093-x. [PubMed: 17024475].
  59. Wang Y, Liu Y, Ji W, Qin H, Wu H, Xu D, et al. Analysis of MTR and MTRR polymorphisms for neural tube defects risk association. Medicine. 2015;94(35). doi: 10.1097/MD.0000000000001367. [PubMed: 26334892].

Iranian Red Crescent Medical Journal (IRCMJ)
Volume 23, Issue 11 - Serial Number 11
2021
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  • Receive Date: 20 July 2021
  • Revise Date: 26 May 2024
  • Accept Date: 27 January 2024
  • First Publish Date: 27 January 2024
  • Publish Date: 01 November 2021
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