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Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy

Abstract

Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C → T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance.

References

  1. 1.

    Jongbloet PH: The effects of preovulatory overripeness of human eggs on development. Aging gametes. Their biology and pathology. International Symposium, Seattle, 1973. Edited by: Blandau RJ. 1975, Basel: Karger, 300-329.

    Google Scholar 

  2. 2.

    Jongbloet PH: The ageing gamete in relation to birth control failures and Down syndrome. Eur J Pediatr. 1985, 144: 343-347. 10.1007/BF00441775.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Jongbloet PH: Prepregnancy care: Background biological effects. Prepregnancy Care: A Manual for Practice. Edited by: Chamberlain G, Lumley J. 1986, New York: Wiley & Sons, 31-52.

    Google Scholar 

  4. 4.

    Jongbloet PH: Over-ripeness ovopathy – A challenging hypothesis for sex ratio modulation. Hum Reprod. 2004, 19: 769-774. 10.1093/humrep/deh136. and 1036–1038.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Morgan HD, Santos F, Green K, Dean W, Reik W: Epigenetic reprogramming in mammals. Hum Molec Genet. 2005, 14: R47-R58. 10.1093/hmg/ddi114.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley MR, Weir DG, Scott JM: Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates; implications for folate intake recommendations. Lancet. 1997, 349: 1591-1593. 10.1016/S0140-6736(96)12049-3.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, Heuvel van den LP, Rozen R: A candidate genetic risk factor for vascular disease: a common mutation in methyleneterahydrofolate reducase. Nat Genet. 1995, 10: 111-113. 10.1038/ng0595-111.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Guéant-Rodriguez R-M, Guéant J-L, Debard R, Thirion S, Hong LX, Bronowicki J-P, Namour F, Chabi NW, Sani A, Anello G, Bosco P, Romano C, Amouzou E, Arrieta HR, Sànchez BE, Romano A, Herbeth B, Guilland J/C, Mutchinick OM: Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations. Am J Clin Nutr. 2006, 83 (3): 701-707.

    Article  PubMed  Google Scholar 

  9. 9.

    Blom HJ, Shaw GM, den Heijer M, Finnell RH: Neural tube defects and folate: case far from closed. Nat Rev/Neurosience. 2006, 7: 724-731. 10.1038/nrn1986.

    Article  CAS  Google Scholar 

  10. 10.

    Bailey LB, Berry RJ: Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriages. Am J Clin Nutr. 2005, 81 (suppl): 1213S-1217S.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Hobbs CA, James SJ, Jernigan S, Melnyk S, Lu Y, Malik S, Cleves MA: Congenital heart defects, maternal homocysteine, smoking, and the 677 C>T polymorphism in the methylenetetrahydrofolate reductase gene: Evaluating gene-environment interactions. Am J Obstet Gynecol. 2006, 194: 218-224. 10.1016/j.ajog.2005.06.016.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Bille C, Murray JC, Olsen SF: Folid acid and birth malformations. BMJ. 2007, 334: 433-434. 10.1136/bmj.39133.386296.BE.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. 13.

    Muntjewerff JW, Kahn RS, Blom HJ, den Heijer M: Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry. 2006, 11 (2): 143-149. 10.1038/sj.mp.4001746.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Zintzaras E: C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta-analysis of genetic association studies. Psychiatr Genet. 2006, 16 (3): 105-115. 10.1097/01.ypg.0000199444.77291.e2.

    Article  PubMed  Google Scholar 

  15. 15.

    Gilbody S, Lewis S, Lightfoot T: Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: A huge review. Am J Epidemiol. 2007, 165: 1-13. 10.1093/aje/kwj347.

    Article  PubMed  Google Scholar 

  16. 16.

    Zintzaras E, Chatzoulis DZ, Karabatsas CH, Stefanidis I: The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type. J Hum Genet. 2005, 50: 267-275. 10.1007/s10038-005-0250-z.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM: Periconceptional multivitamin use reduces the risk of preeclampsia. Am J Epidemiol. 2006, 164: 470-477. 10.1093/aje/kwj218.

    Article  PubMed  Google Scholar 

  18. 18.

    Chavarro JE, Rich-Edwards JW, Rosner BA, Wilett WC: Use of multivitamins, intake of B vitamins, and risk of ovulatory infertility. Fertil Steril. 2007, 89 (3): 668-676. 10.1016/j.fertnstert.2007.03.089.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    den Heijer M, Lewington S, Clarke R: Homocysteine, MTHFR and risk of venous thrombosis: a metaanalysis of published epidemiological studies. J Thromb Haemost. 2005, 3: 292-299. 10.1111/j.1538-7836.2005.01141.x.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Cronin S, Furie KL, Kelly PJ: Dose-related association of MTHFR 677T allele with risk of ischemic stroke Evidence from a cumulative meta-analysis. Stroke. 2005, 36: 1581-1587. 10.1161/01.STR.0000169946.31639.af.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Födinger M, Sunder-Plassmann G: Methylenetetrahydrofolate reductase polymorphisms and renal failure. MTHFR polymorphisms and Disease. Edited by: Ueland PM, Rozen R. 2005, Georgetown, Texas, USA: Eurekah.com/Landes Bioscience, 170-178.

    Google Scholar 

  22. 22.

    Elias MF, Sullivan LM, D'Agostino RB, Elias PK, Jacques PF, Selhub J, Seshadri S, et al: Homocysteine and cognitive performance in the Framingham offspring study: Age is important. Am J Epidemiol. 2005, 162: 644-653. 10.1093/aje/kwi259.

    Article  PubMed  Google Scholar 

  23. 23.

    Clarke R: Commentary: An updated review of the published studies of homocysteine and cardiovascular disease. Int J Epidemiol. 2002, 31: 70-71. 10.1093/ije/31.1.70.

    Article  PubMed  Google Scholar 

  24. 24.

    Clarke R: Homocysteine, B vitamins, and the risk of dementia. Am J Nutr. 2007, 85 (2): 329-330.

    Article  CAS  Google Scholar 

  25. 25.

    Davey Smith G, Ebrahim S: Folate supplementation and cardiovascular disease. Lancet. 2005, 366: 1679-1681. 10.1016/S0140-6736(05)67676-3.

    Article  PubMed  Google Scholar 

  26. 26.

    Wald DS, Moris JK, Law M, Wald NJ: Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence. BMJ. 2006, 333: 1114-1117. 10.1136/bmj.39000.486701.68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Zintzaras E: Methylenetetrahydrofolate reductase (MTHFR) gene and susceptibility to breast cancer: A meta-analysis. Clin Genet. 2006, 69: 327-336. 10.1111/j.1399-0004.2006.00605.x.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Zintzaras E: Associations of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: a meta-analysis. J Hum Genet. 51: 618-624. 10.1007/s10038-006-0405-6.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

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

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Crott JW, Mason JB: MTHFR Polymorphisms and colorectal neoplasia. MTHFR polymorphisms and Disease. Edited by: Ueland PM, Rozen R. 2005, Georgetown, Texas, USA: Eurekah.com/Landes Bioscience, 178-196.

    Google Scholar 

  31. 31.

    Venners SA, Liu X, Perry MJ, Korrick SA, Li Z, Yang F, Yang J, Lasley BL, Xu X, Wang X: Urinary estrogen and progesterone metabolite concentrations in menstrual cycles of fertile women with non-conception, early pregnancy loss or clinical pregnancy. Hum Reprod. 2006, 21: 2272-2280. 10.1093/humrep/del187.

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Selevan SG, Lemasters GK: The dose-response fallacy in human reproductive studies of toxic exposures. J Occup Med. 1987, 29: 451-455.

    PubMed  CAS  Google Scholar 

  33. 33.

    Wynn M, Wynn A: No nation can rise above the level of women: New thoughts on maternal nutrition. The Caroline Walker Lecture. 1993, London: Caroline Walker Trust, 1-30.

    Google Scholar 

  34. 34.

    Young SS, Eskenzi B, Marchetti FM, Block G, Wyrobek AJ: The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men. Hum Reprod. 2008, 23: 1014-1022. 10.1093/humrep/den036.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Li D, Pickel L, Liu Y, Wu Q, Cohn JS, Rozen R: Maternal methylenetetrahydrofolate reductase deficiency and low dietary folate lead to adverse reproductive outcomes and congenital heart defects in mice. Am J Clin Nutr. 2005, 82: 188-195.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Ferguson SE, Smith GN, Walker MC: Maternal plasma homocysteine levels in women with preterm premature rupture of membranes. Med Hypoth. 2001, 56: 85-90. 10.1054/mehy.2000.1116.

    Article  CAS  Google Scholar 

  37. 37.

    George L, Mills JL, Johansson ALV, Nordmark A, Olander B, Granath F, Cnattingius S: Plasma folate levels and risk of spontaneous abortion. JAMA. 2002, 288: 1867-1873. 10.1001/jama.288.15.1867.

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Nelen WLDM, Blom HJ: Pregnancy complications. MTHFR polymorphisms and Disease. Edited by: Ueland PM, Rozen R. 2005, Georgetown, Texas, USA: Eurekah.com/Landes Bioscience, 144-162.

    Google Scholar 

  39. 39.

    Ren A, Wang J: Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: A meta-analysis. Fertil Steril. 2006, 86: 1716-1722. 10.1016/j.fertnstert.2006.05.052.

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Isotalo PA, Wells GA, Donelly JG: Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: An examination of C677T and A1298C mutations. Am J Hum Genet. 2000, 67: 986-990. 10.1086/303082.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. 41.

    Isotalo PA, Donnelly JG: Prevalence of methylenetetrahydrofolate reductase mutations in patients with venous thrombosis. Molec Diag. 2000, 5: 59-66.

    Article  CAS  Google Scholar 

  42. 42.

    Zetterberg H, Regland B, Palmer M, Ricksten A, Palmqvist L, Rymo L, Arvanitis DA, Spandilos DA, Blennow K: Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneous aborted embryos. Eur J Hum Genet. 2002, 10: 113-118. 10.1038/sj.ejhg.5200767.

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Bae J, Shin SJ, Cha SH, Choi DH, Lee S, Kim NK: Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) in spontaneously aborted embryos. Fertil Steril. 2007, 87: 351-355. 10.1016/j.fertnstert.2006.06.027.

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Jugessur A, Wilcox AJ, Lie RT, Murray JC, Taylor JA, Ulvik A, Devron CA, Vindenes HA, Åbyholm FE: Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads. Am J Epidemiol. 2003, 157: 1083-1091. 10.1093/aje/kwg097.

    Article  PubMed  Google Scholar 

  45. 45.

    van Beynum IM, Kapusta L, den Heyer M, Vermeulen SHHM, Kouwenberg M, Daniëls O, Blom HJ: Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation. Eur Heart J. 2006, 27: 981-987. 10.1093/eurheartj/ehi815.

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Jongbloet PH: Non-optimal maturation of the oocyte, maternal MTHFR polymorphisms, periconceptional folate, and decrease of congenital heart defects. Eur Heart J. 2007, 28: 2043-10.1093/eurheartj/ehm235.

    Article  PubMed  Google Scholar 

  47. 47.

    Rozen R, Clarke Frazer F, Shaw G: Decreased proportion of female newborn infants homozygous for the 677C → T mutation in methylenetetrahydrofolate reductase. Am J Med Genet. 1999, 83: 142-143. 10.1002/(SICI)1096-8628(19990312)83:2<142::AID-AJMG12>3.0.CO;2-Y.

    Article  PubMed  CAS  Google Scholar 

  48. 48.

    Dobson AT, Davis RM, Rosen MP, Shen S, Rinaudo PF, Chan J, Cedars MI: Methyltetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF. Hum Reprod. 2007, 22: 450-456. 10.1093/humrep/del396.

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    Miettinen OS, Reiner ML, Nadas AS: Seasonal incidence of coarctation of the aorta. Br Heart J. 1970, 32: 103-107. 10.1136/hrt.32.1.103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 50.

    Pallast EMG, Jongbloet PH, Straatman HM, Zielhuis GA: Excess seasonality of births among patients with schizophrenia and seasonal ovopathy. Schizophr Bull. 1994, 20: 269-227.

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Marzullo G, Clarke Fraser F: Similar rhythmsof seasonal conceptions in neural tube defects and schizophrenia: A hypothesis of oxidant stress and the photoperiod. Birth Def Res (part A). 2005, 73: 1-5. 10.1002/bdra.20100.

    Article  CAS  Google Scholar 

  52. 52.

    Jongbloet PH, van Soestbergen M, Veen van der EA: Month-of-birth distribution of diabetics and ovopathy: A new aetiological view. Diabetes Res. 1988, 9 (2): 51-58.

    PubMed  CAS  Google Scholar 

  53. 53.

    Jongbloet PH, Groenewoud HMM, Roeleveld N: Seasonally bound ovopathy versus "Temperature at conception" as cause for anorexia nervosa and othe eating disorders. Int J Eat Disord. 2005, 38: 236-243. 10.1002/eat.20173.

    Article  PubMed  Google Scholar 

  54. 54.

    Jongbloet PH, Groenewoud HMM, Huber S, Fieder M, Roeleveld N: Month of birth related to fecundity and childlessness among contemporary women. Hum Biol. 2007, 79: 479-490.

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Allen C, Reardon W: Assisted reproduction technology and defects of genomic imprinting. BJOG. 2005, 112 (12): 1589-1594. 10.1111/j.1471-0528.2005.00784.x.

    Article  PubMed  Google Scholar 

  56. 56.

    Horsthemke B, Ludwig M: Assisted reproduction: The epigenetic perspective. Hum Reprod. 2005, 11: 473-482. 10.1093/humupd/dmi022.

    Article  Google Scholar 

  57. 57.

    Kelly TLJ, Trasler JM: Developmental biology: frontiers for clinical genetics. Clin Genet. 2004, 65: 247-260. 10.1111/j.0009-9163.2004.00236.x.

    Article  PubMed  CAS  Google Scholar 

  58. 58.

    Chang AS, Moley KH, Wangler M, Feinberg AP, Debaun MR: Association between Beckwith-Wiedemann syndrome and assisted reproductive technology: a case series of 19 patients. Fertil Steril. 2005, 83: 349-354. 10.1016/j.fertnstert.2004.07.964.

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Wieczorek D, Ludwig M, Boehringer S, Jongbloet PH, Gillessen-Kaesbach G, Horsthemke B: Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome. Hum Genet. 2007, 121: 369-376. 10.1007/s00439-007-0336-0.

    Article  PubMed  Google Scholar 

  60. 60.

    Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, Thurston A, Huntley JF, Rees WD, Maloney CA, Lea RG, Craigon J, McEvoy TG, Young LE: DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. PNAS. 2007, 104: 19351-19356. 10.1073/pnas.0707258104.

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Cooney CA, Dave AA, Wolff GL: Maternal methyl supplements inmice affect epigentic variation and DNA methylation of offspring. J Nutr. 2002, 132: 2393S-2400S.

    Article  CAS  PubMed  Google Scholar 

  62. 62.

    DeBaun MR, Chang AS: Epigenetics and assisted reproductive technology. Fertil Steril. 2006, 85: 269-270. 10.1016/j.fertnstert.2005.10.006.

    Article  Google Scholar 

  63. 63.

    Linden van der IJM, Smulders YM, Kok RM, van Beynum IM, den Heyer M, Blom JH: Decreased global DNA methylation in spina bifida patients. One-Carbon Metabolism and Neural Tube defects. 2008, Thesis Radboud University Nijmegen, 89-96. ISBN 978-90-6464-193-0.

    Google Scholar 

  64. 64.

    Crow T: Genes for schizophrenia. Lancet. 2003, 366: 1829-1830. 10.1016/S0140-6736(03)13433-2.

    Article  Google Scholar 

  65. 65.

    Stams WA, Den Boer ML, Beverloo HB, Meijerink JP, Van Wering ER, Janka-Schaub GE, Pieters R: Expression levels of Tel, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in T(12;21)-positive pediatric acute lymphoblastic leukemia. Clin Cancer Res. 2005, 11: 2974-2980. 10.1158/1078-0432.CCR-04-1829.

    Article  PubMed  CAS  Google Scholar 

  66. 66.

    James SJ: The molecular dynamics of abnormal folate metabolism and DNA methylation; implications for disease susceptibility and progression. MTHFR polymorphisms and Disease. Edited by: Ueland PM, Rozen R. 2005, Georgetown, Texas, USA: Eurekah.com/Landes Bioscience, 78-99.

    Google Scholar 

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Wim Lemmens contributed towards the design of the figures.

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Correspondence to Piet Hein Jongbloet.

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The content of this manuscript was subject of the fare-well lecture of PHJ on 12th of June 2007 at the Department of Epidemiology, Biostatistics, and Health Technology Assessment at the Radboud University Nijmegen, the Netherlands. The co-authors AV, MdH, and NR participated in the design of the study and the coordination for the manuscript preparation. They revised it critically for important intellectual content and interpretation of the arguments. All authors read and approved the final manuscript.

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Jongbloet, P.H., Verbeek, A.L., den Heijer, M. et al. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy . J Exp Clin Assist Reprod 5, 5 (2008). https://doi.org/10.1186/1743-1050-5-5

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