Clinical and Experimental Reproductive Medicine

The Korean Society for Reproductive Medicine (대한생식의학회)
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The Analysis of Interrelationship between Homocysteine and Methylenetetrahydrofolate Reductase Mutation in Patients with Recurrent Spontaneous Abortion

반복자연유산 환자에서 Homocysteine과 Methylenetetrahydrofolate Reductase 돌연변이의 상관관계에 대한 분석

  • Nam, Yoon-Sung (Department of Obstetrics and Gynecology, College of Medicine, Pocheon CHA University) ;
  • Cha, Kwang-Yul (Department of Obstetrics and Gynecology, College of Medicine, Pocheon CHA University) ;
  • Kim, Nam-Keun (Institute for Clinical Research, College of Medicine, Pocheon CHA University) ;
  • Kang, Myung-Seo (Institute for Clinical Research, College of Medicine, Pocheon CHA University) ;
  • Kim, Se-Hyun (Institute for Clinical Research, College of Medicine, Pocheon CHA University) ;
  • Oh, Do-Yeon (Institute for Clinical Research, College of Medicine, Pocheon CHA University)
  • 남윤성 (포천중문 의과대학 산부인과학교실) ;
  • 차광렬 (포천중문 의과대학 산부인과학교실) ;
  • 김남근 (포천중문 의과대학 임상의학연구소) ;
  • 강명서 (포천중문 의과대학 임상의학연구소) ;
  • 김세현 (포천중문 의과대학 임상의학연구소) ;
  • 오도연 (포천중문 의과대학 임상의학연구소)
  • Published : 2002.09.30
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Abstract

Objective : To analyze the interrelationship between homocysteine and methylenetetrahydrofolate reductase (MTHFR) mutation in patients with recurrent spontaneous abortion. Material and Method: Homocysteine and MTHFR mutation were tested by fluorescent polarizing immunoassay and PCR-RFLP method, respectively. Results: In patients with homocysteine level less than 5 ?mol/L, there was no case of normal group but there were four cases of heterozygosity and one case of homozygosity. In patients with homocysteine level 5$\sim$10 ? mol/L, the number of normal, heterozygosity and homozygosity group were eleven, eighteen and eight, respectively. In patients with homocysteine level $10{\sim}15$ ? mol/L, the number of normal, heterozygosity and homozygosity group were four, one and one, respectively. In patients with homocysteine level more than 15 ? mol/L, there was no case of normal and heterozygosity group but there were two cases of homozygosity. Conclusions: Hyperhomocysteinemia due to MTHFR mutation is a cause of recurrent spontaneous abortion. And there was a significant relationship between homocysteine and MTHFR mutation.

Keywords

References

  1. Malinow MR, Bostom AG, Krauss RM. Homocysteine, diet, and cardiovascular disease. A healthcare statement for healthcare professionals from the nutrition committee. American Heart Association. Circulation 1999; 99: 178-82
  2. Ubbink JB. Homocysteine - an atherogenic and a thrombogenic factor? Nutr Rev 1995; 53: 323-5
  3. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996; 27: 517-27 https://doi.org/10.1016/0735-1097(95)00508-0
  4. Olszewski AJ, McCully KS. Homocysteine metabolism and the oxidative modification of proteins and lipids. Free Rad Biol Med 1993; 14: 683-93 https://doi.org/10.1016/0891-5849(93)90151-J
  5. D'Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood 1997; 90: 1-11
  6. McCully KS. Chemical pathology of homocysteine. Ann Clin Lab Sci 1994; 24: 27-59
  7. Ubbink JB. Vitamin nutrition status and homocysteine: an atherogenic risk factor. Nutr Rev 1994; 52: 383-93 https://doi.org/10.1111/j.1753-4887.1994.tb01369.x
  8. Nordstrom M, Kellstrom T. Age dependency of cystathionine ?-synthase activity in human fibroblasts in homocysteinemia and atherosclerotic vascular disease. Atherosclerosis 1992; 94: 213-21 https://doi.org/10.1016/0021-9150(92)90246-D
  9. Masser P, Taylor LM, Porter JM. Importance of elevated homocysteine concentrations as a risk factor for atherosclerosis. Ann Thorac Surg 1994; 58: 1240-6 https://doi.org/10.1016/0003-4975(94)90522-3
  10. Guttormsen A, Nesthus I, Uleland P, Nygard O, Schneede J, Vollset SE, et al. Determinants and vitamin resp onsiveness of intermediate hyperhomocysteinemia (>40 ? mol/L). J Clin Invest 1996; 68: 2174-83
  11. Blom HJ, Kleinveld HA, Boers GHJ, Demacker PNM, Hak-Lemmers HLM, Poele-Pothoff MTWB, et al. Lipid peroxidation and susceptibility of low density lipoprotein to in vitro oxidation in hyperhomocysteinemia. Eur J Clin Invest 1995; 25: 149-54 https://doi.org/10.1111/j.1365-2362.1995.tb01541.x
  12. Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PWF, Belanger AJ, et al. Association between plasma homocysteine concentration and extracranial carotid artery stenosis. N Engl J Med 1995; 332: 286-91 https://doi.org/10.1056/NEJM199502023320502
  13. Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, et al. Reduction of plasma homocysteine concentrations by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998; 338: 1009-15 https://doi.org/10.1056/NEJM199804093381501
  14. Tucker KL, Mahnken B, Wilson WF, Jacques P, Selhub J. Folic acid fortification of the food supply: Potential benefits and risk for the elderly population. JAMA 1996; 276: 1879-85 https://doi.org/10.1001/jama.276.23.1879
  15. Franken PDG, Boers GHJ, Blom HJ, Cruysberg JRM, Trijbels FJM, Hamel BCJ. Prevalence of familial mild hyperhomocysteinemia. Atherosclerosis 1996; 125: 71-80 https://doi.org/10.1016/0021-9150(96)05849-2
  16. Glueck CJ, Shaw P, Lang JE, Tracy T, Sieve-Smith L, Wang Y. Evidence that homocysteine is an independent risk factor for at herosclerosis in hyperlipidemic patients. Am J Cardiol 1995; 75: 132-6 https://doi.org/10.1016/S0002-9149(00)80061-2
  17. Kang SS, Wong PWK, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary disease. Am J Hum Genet 1991; 48: 536-45
  18. Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93: 7-9 https://doi.org/10.1161/01.CIR.93.1.7
  19. Mandel H, Brenner B, Berant M. Coexistence of hereditary homocystinuria and factor V Leiden-effect on thrombosis. N Engl J Med 1996; 334: 763-8 https://doi.org/10.1056/NEJM199603213341204
  20. Selhub J, D'Angelo A. Hyperhomocysteinemia and thrombosis: acquired conditions. Thromb Haemost 1997; 78: 527-31
  21. Zighetti ML, Cattaneo M, Tsai MY. A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep vein thrombosis in patients with mutant factor V (factor V: $Q^{506}$). Thromb Haemost 1997; Supplement: 570
  22. den Heijer M, Koster T, Blom HJ. Hyperhomocysteinemia as a risk factor for deep vein thrombosis. N Engl J Med 1996; 334: 759-62 https://doi.org/10.1056/NEJM199603213341203
  23. Van der Put NMJ, Steegers-Theunissen RPM, Frosst P, Trijbels FJM, Eskes TKAB, van den Heuvel LP, et al. Mutated methy lenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995; 346: 1070-1 https://doi.org/10.1016/S0140-6736(95)91743-8
  24. Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in U.S. physicians. Circulation 1996; 94: 2410-6 https://doi.org/10.1161/01.CIR.94.10.2410
  25. Carey MC, Donovan DE, FutzGerald O, McAuley FD. Homocystinuria: A clinical and pathological study of nine subjects in six families. Am J Med 1968; 48: 7-25
  26. Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH. Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem 1993; 39: 1764-79
  27. Kang SS, Wong PW, Manilow MR. Homocysteinemia as a risk factor for occlusive vascular disease. Ann Rev Nutr 1992; 12: 279-98 https://doi.org/10.1146/annurev.nu.12.070192.001431
  28. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine / homocysteine metabolism in premature vascular disease: its occurrence, cofactor therapy and enzymology. Arterioscler Thromb 1993; 13: 1253-60 https://doi.org/10.1161/01.ATV.13.9.1253
  29. Brenner B, Sarig G, Weinner Z, Younis Y, Blumfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82: 6-9
  30. Girling J, de Swiet M. Inherited thrombophilia and pregnancy. Curr Opin Obstet Gynecol 1998; 10: 135-44 https://doi.org/10.1097/00001703-199804000-00010
  31. Nelson WLDM, Steegers EAP, Eskes TKAB, Blom JH. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 1997; 350: 861
  32. Nelen WLDM, Heil SG, Steegers EAP, Eskes TKAB. Recurrent early pregnancy loss and genetic- related disturbances in folate and homocysteine metabolism. Br J Hosp Med 1997; 58: 511-3
  33. Dekker GA, de Vries JIP, Doelitzsch PM, Huijgens PC, von Blomberg BME, Kakobs C, et al. Underlying disorders associated with severe early onset preeclampsia. Am J Obstet Gynecol 1995; 173: 1042-8 https://doi.org/10.1016/0002-9378(95)91324-6
  34. de Vries JIP, Dekker GA, Huijgens PC, Jakobs C, Blomberg BME, van Geijn HP. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynecol 1997; 104: 1248-54 https://doi.org/10.1111/j.1471-0528.1997.tb10970.x
  35. Nelen WLDM, Blom HJ, Steegers EAP, Heijer MD, Eskes TKAB. Hyperhomocysteinemia and recurrent early pregnancy loss: meta-analysis. Fertil Steril 2000; 74: 1196-9 https://doi.org/10.1016/S0015-0282(00)01595-8
  36. Welch GN, Upchurch GR, Loscalzo J. Homocysteine, oxidative stress, and vascular disease. Hosp Pract 1997; 70: 87-92
  37. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic and intakes. JAMA 1995; 274: 1049-57 https://doi.org/10.1001/jama.274.13.1049
  38. Ubbink J, Vermaak W, Van der Merwe A, Becker P, Delport R, Potgeiter H. Vitamin requirements for the treatment of hyperhomocysteinaemia in humans. J Nutr 1994; 124: 1927-33 https://doi.org/10.1093/jn/124.10.1927
  39. Malinow R, Javier F, Szklo M, Chambless LE, Bond G. Carotid artery intimal-medial wall thickening and plasma homocysteine in asymptomatic adults. Circulation 1993; 87: 1107-13 https://doi.org/10.1161/01.CIR.87.4.1107
  40. Robinson K, Mayer EL, Miller DP, Green R, Van-Lente F, Gupta A, et al. Hyperhomocysteinaemia and low pyridoxal phosphate. Circulation 1995; 92: 2825-30 https://doi.org/10.1161/01.CIR.92.10.2825