Clinical and Experimental Reproductive Medicine

The Korean Society for Reproductive Medicine (대한생식의학회)
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Polymorphisms of 5,10-Methylenetetrahydrofolate Reductase (MTHFR C677T and A1298C) Gene in Recurrent Spontaneous Abortion

5,10-Methylenetetrahydrofolate Reductase (MTHFR C677T와 A1298C) 유전자 돌연변이의 반복자연유산 관련성 연구

  • Kim, Nam-Keun (Institute for Clinical Research, College of Medicine, Pochon CHA University) ;
  • Nam, Yoon-Sung (Infertility Medical Center, CHA General Hospital) ;
  • Lee, Su-Man (Infertility Medical Center, CHA General Hospital) ;
  • Kim, Sun-Hee (Institute for Clinical Research, College of Medicine, Pochon CHA University) ;
  • Shin, Seung-Joo (Department of Obstetrics and Gynecology, College of Medicine, Pochon CHA University) ;
  • Chang, Sung-Woon (Department of Obstetrics and Gynecology, College of Medicine, Pochon CHA University) ;
  • Kim, Se-Hyun (Department of Preventive, College of Medicine, Pochon CHA University) ;
  • Cha, Kwang-Yul (Infertility Medical Center, CHA General Hospital) ;
  • Oh, Do-Yeun (Institute for Clinical Research, College of Medicine, Pochon CHA University)
  • 김남근 (포천중문 의과대학교 임상의학연구소) ;
  • 남윤성 (차병원 여성의학연구소) ;
  • 이수만 (차병원 여성의학연구소) ;
  • 김선희 (포천중문 의과대학교 임상의학연구소) ;
  • 신승주 (포천중문 의과대학교 분당 차병원 산부인과) ;
  • 장성운 (포천중문 의과대학교 분당 차병원 산부인과) ;
  • 김세현 (포천중문 의과대학교 예방의학교실) ;
  • 차광렬 (차병원 여성의학연구소) ;
  • 오도연 (포천중문 의과대학교 임상의학연구소)
  • Published : 2002.09.30
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Abstract

Objective : Previous studies have suggested that hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR C677T) mutations are associated with increased risk of recurrent spontaneous abortion (RSA). Recently, a second site polymorphism in MTHFR, 1298A-->C, which changes a glutamic acid into an alanine residue, was shown to be associated with a decreased enzyme activity. We tested whether the variant alleles of MTHFR C677T and A1298C are risk factor (biomarker) for RSA. Materials and Methods: We analyzed DNA from a case-control study in the Korean DNA was extracted from blood samples of 118 patients with RSA and 123 healthy fertile patients as the controls. MTHFR variant alleles were determined by a PCR-restriction fragment length polymorphism assay. Results: We found no evidence for an association between 677TT genotype and risk of RSA (OR=1.95, 95% CI=$0.84{\sim}4.50$, p=0.12). However, the MTHFR 1298AC (OR=0.36, 95% CI=$0.20{\sim}0.63$, p=0.0004) and 1298AC+CC (OR=0.35, 95% CI=$0.20{\sim}0.61$, p=0.0002) genotypes were lower among 118 RSA cases compared with 123 controls, conferring a 2.8-fold decrease in risk of RSA, respectively. Moreover, the combined genotypes of MTHFR 677CC/1298AC (OR=0.30, 95% CI=$0.10{\sim}0.88$, p=0.029) and 677CT/1298AC (OR=0.77, 95% CI=$0.60{\sim}0.99$, p=0.043) also showed significantly lower risk than those with MTHFR 677CC/1298AA type. Conclusion: MTHFR 1298AC, MTHFR 677CC/1298AC and 677CT/1298AC genotypes may represent genetic markers for the protection of RSA at least in Korean women.

Keywords

References

  1. Younis JS, Ohel G, Brenner B, Ben-Ami M. Familial thrombophilia--the scientific rationale for thrombophylaxis in recurrent pregnancy loss? Hum Reprod 1997; 12(7): 1389-90
  2. Raziel A, Kornberg Y, Friedler S, Schachter M, Sela BA, Ron-El R. Hypercoagulable thrombophilic defects and hyperhomocysteinemia in patients with recurrent pregnancy loss. Am J Reprod Immunol 2001; 45(2): 65-71 https://doi.org/10.1111/j.8755-8920.2001.450201.x
  3. Yamada H, Kato EH, Kobashi G, Ebina Y, Shimada S, Sakuragi N, Fujimoto S. Recurrent pregnancy loss: Etiology of thrombophilia. Semin Thromb Hemost 2001; 27: 121-9 https://doi.org/10.1055/s-2001-14070
  4. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56: 111-28
  5. Loscalzo J. The oxidant stress of hyperhomocyst (e)inemia. J Clin Invest 1996; 98: 5-7 https://doi.org/10.1172/JCI118776
  6. Chango A, Boisson F, Barbe F, Quilliot D, Droesch S, Pfister M, Fillon-Emery N, Lambert D, Fremont S, Rosenblatt DS, Nicolas JP. The effect of 677 C-->T and 1298A-->C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr 2000; 83(6): 593-6 https://doi.org/10.1017/S0007114500000751
  7. Fodinger M, Wagner OF, Horl WH, Sunder-Plassmann G. Recent insights into the molecular genetics of the homocysteine metabolism. Kidney Int 59 Supp1 2001; 78: S238-42
  8. Jakubowski H, Zhang L, Bardeguez A, Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothilial cells: implications for atherosclerosis. Circ Res 2000; 87(1): 45-57 https://doi.org/10.1161/01.RES.87.1.45
  9. Matsuo K, Suzuki R, Hamajima N, Ogura M, Kagami Y, Taji H, Kondoh E, Maeda S, Asakura S, Kaba S, Nakamura S, Seto M, Morishima Y, Tajima K. Association between polymorphisms of folateand methionine- metabolizing enzymes and susceptibility to malignant ly mphoma. Blood 2001; 97(10): 3205-9 https://doi.org/10.1182/blood.V97.10.3205
  10. Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 1991; 48(3): 536-45
  11. Frosst P, Ma HJ, Milos R, Goytte P, Sheppard CA, Matthew Boers GJH, den Heijer M, Kluijtmans AJ, van der Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3 https://doi.org/10.1038/ng0595-111
  12. van der Put NMJ, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van der Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural tube defects? Am J Hum Genet 1998; 62: 1044-51
  13. Kim NK, Kang GD, Kim HJ, Kim SH, Nam YS, Lee S, Chung HM, Kang SH, Ahn JY, Choi BO, Hwang SG, Oh D. Genetic polymorphisms of 5, 10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) in healthy Korean. Korean J Genetics 2002; 24(2): 227-34
  14. de Franchis R, Mancini FP, D'Angelo A, Sebastio G, Fermo I, de Stefano V, Margaglione M, Mazzola G, di Minno G, Andria G. Elevated total plasma homocysteine and 677C-->T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease. Am J Hum Genet 1996; 59(1): 262-4
  15. Jacques PF, Rosenberg IH, Rogers G, Selhub J, Bowman BA, Gunter EW, Wright JD, Johnson CL. Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr 1999a; 69(3): 482-9 https://doi.org/10.1093/ajcn/69.3.482
  16. Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR, Heistad DD. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest 1996; 98(1): 24-9 https://doi.org/10.1172/JCI118771
  17. Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM. Reduction of plasma homocyst (e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998; 338(15): 1009-15 https://doi.org/10.1056/NEJM199804093381501
  18. Nelen WLDM, Blom HJ, Thomas CMG, Steegers EAP, Boers GHJ, Eskes TKAB. Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. J Nutr 1998; 128: 1336-41
  19. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999b; 340(19): 1449-54 https://doi.org/10.1056/NEJM199905133401901
  20. Murua AL, Quintana I, Janson J, Batista M, Camera MI, Kordich LC. Plasmatic homocysteine response to vitamin supplementation in elderly people. Thromb Res 2000; 100(6): 495-500 https://doi.org/10.1016/S0049-3848(00)00360-1
  21. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy. Lancet 1999; 340(1): 9-13 https://doi.org/10.1016/0140-6736(92)92423-D
  22. Nelen WL, Steegers EA, Eskes TK, Blom HJ. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 1997; 350(9081): 861
  23. Nelen WLDM, Blom HJ, Steegers EAP, den Heijer M, Eskes TKAB. Hyperhomocysteinemia and recurrent early pregnancy loss. Fertil Steril 2000; 74(6): 1196-9 https://doi.org/10.1016/S0015-0282(00)01595-8
  24. Quere I, Bellet H, Hoffet M, Janbon C, Mares P, Gris JC. A women with five consecutive fetal deaths: case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages. Fertil Steril 1998; 69(1): 152-4 https://doi.org/10.1016/S0015-0282(97)00451-2
  25. Isotalo PA, Wells GA, Donnelly JG. Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: an examination of C677T and A1298C mutation. Am J Hum Genet 2000; 67(4): 986-90 https://doi.org/10.1086/303082
  26. Rosenberg N, Murata M, Ikeda Y, Opare-Sem O, Zivelin A, Geffen E, Seligsohn U. The frequent 5, 10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common hyplotype in whites, Japanese, and Africans. Am J Hum Genet 2002; 70: 758-62 https://doi.org/10.1086/338932
  27. Holmes ZR, Regan L, Chilcott I, Cohen H. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss. British J Haematol 1999; 105: 98-101 https://doi.org/10.1111/j.1365-2141.1999.01319.x
  28. Lissak A, Sharon A, Fruchter O, Kassel A, Sanderovitz J, Abramovici H. Polymorphism for mutation of cytosine to thymine at location 677 in the methylenetetrahydrofolate reductase gene is associated with recurrent early fetal loss. Am J Obstet Gynecol 1999; 181(1): 126-30 https://doi.org/10.1016/S0002-9378(99)70447-3
  29. Grandone E. Methylenetetrahydrofolate reductase (MTHFR) 677T->C mutation and unexplained early pregnancy loss. Thromb Haemost 1998; 79: 1056-7
  30. Murphy RP, Donoghue C, Nallen RJ, D'Mello M, Regan C, Whitehead AS, Fitzgerald DJ. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphism in pregnancy. Artherioscler Thromb Vasc Biol 1999; 20: 266-70
  31. Foka ZJ, Lambropoulos AF, Saravelos H, Karas GB, Karavida A, Agorastos T, Zournatzi V, Makris PE, Bontis J, Kotsis A. Factor V leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod 2000; 15(2): 458-62 https://doi.org/10.1093/humrep/15.2.458
  32. Nam YS, Cha KY, Kim NK, Kim SH, Lim JW, Kang GD, Kang MS, Kim SH, Oh D. The analysis of methylenetetrahydrofolate reductase mutation in recurrent spontaneous abortion. Kor J Fertil Steril 2001; 28(3): 247-53
  33. Kutteh WH, Park VM, Deither SR. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 1999; 71(6): 1048-53 https://doi.org/10.1016/S0015-0282(99)00133-8
  34. Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82(1): 6-9
  35. Kluijtmans LA, Boers GH, Verbruggen B, Trijbels FJ, Novakova IR, Blom HJ. Homozygous cystathionine beta-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis. Blood 1998; 91(6): 2015-8
  36. Eskes TK. Homocysteine and human reproduction. Clin Exp Obstet Gynecol 2000; 27(3-4): 157-67
  37. van der Molen EF, Arends GE, Nelen EL, van der Put NJ, Heil SG, Eskes TK, Blom HJ. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene as a new risk factor for placental vasculopathy. Am J Obstet Gynecol 2000; 182(5): 1258-63 https://doi.org/10.1067/mob.2000.105199
  38. Gebhardt GS, Scholtz CL, Hillermann R, Odendaal HJ. Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placenta but not with intrauterine growth restriction. Eur J Obstet Gynecol Reprod Biol 2001; 97: 174-7 https://doi.org/10.1016/S0301-2115(00)00540-6
  39. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G. Polymorphism in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 1999; 96: 12810-5 https://doi.org/10.1073/pnas.96.22.12810
  40. Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH, Rozen R. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997; 57(6): 1098-102
  41. Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, Colditz GA, Spiegelman D, Willett WC, Hunter DJ. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 1996; 56: 4862-4
  42. Chen J, Giovannucci EL, Hunter DJ. MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among U.S. men and women: an example of gene-environment interactions in colorectal tumorigenesis. J Nutr 1999; 129 (2S Suppl): S560-4
  43. Nappo F, De Rosa N, Marfella R, De Lucia D, Ingrosso D, Perna AF, Farzati B, Giugliano D. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999; 281(22): 2113-8 https://doi.org/10.1001/jama.281.22.2113
  44. Wouters MGAJ, Thomas CMG, Boers GHJ, Borm GF, Blom HJ, Steegers-Theunissen RPM, Trijbels FJM, Eskes TKAB. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 1993; 60(5): 820-5 https://doi.org/10.1016/S0015-0282(16)56282-7
  45. Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci 2001; 98(7): 4004-9 https://doi.org/10.1073/pnas.061408298