Clinical and Experimental Reproductive Medicine

The Korean Society for Reproductive Medicine (대한생식의학회)
권호 표지
DOI QR코드

DOI QR Code

The role of methylenetetrahydrofolate reductase C677T polymorphism on the peripheral blood natural killer cell proportion in women with unexplained recurrent miscarriages

  • Park, Chan-Woo (Division of Reproductive Endocrinology and Infertility, Cheil General Hospital, Kwandong University College of Medicine) ;
  • Han, Ae-Ra (Division of Reproductive Endocrinology and Infertility, Cheil General Hospital, Kwandong University College of Medicine) ;
  • Kim, Joanne-Kwak (Reproductive Medicine, Department of Obstetrics and Gynecology, Chicago Medical School at Rosalind Franklin University of Medicine and Science) ;
  • Park, So-Yeon (Laboratory of Medical Genetics, Cheil General Hospital, Kwandong University College of Medicine) ;
  • Han, Jung-Yeol (Division of Feto-maternal Medicine, Department of Obstetrics and Gynecology, Cheil General Hospital, Kwandong University College of Medicine) ;
  • Koong, Mi-Kyoung (Division of Reproductive Endocrinology and Infertility, Cheil General Hospital, Kwandong University College of Medicine) ;
  • Song, In-Ok (Division of Reproductive Endocrinology and Infertility, Cheil General Hospital, Kwandong University College of Medicine) ;
  • Yang, Kwang-Moon (Division of Reproductive Endocrinology and Infertility, Cheil General Hospital, Kwandong University College of Medicine)
  • Received : 2011.04.20
  • Accepted : 2011.09.09
  • Published : 2011.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Objective: To examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and hyperhomocysteinemia in women with unexplained recurrent miscarriages (RM) and to investigate the association between MTHFR genotype variants and alloimmune activation, proportion of peripheral blood natural killer (pbNK) cells. Methods: A total of 39 patients with a history of two or more unexplained miscarriages were recruited to this study. The controls were women who had a live birth without a history of RM (n=50). The proportion of pbNK cells was measured by flow cytometry. Plasma homocysteine levels and the incidence of the MTHFR variant of the RM and control groups were compared. The proportion of pbNK cells was compared to the MTHFR variants in the RM group. Results: No differences were found between the two groups' mean plasma homocysteine levels ($7.6{\pm}1.5{\mu}mol$/L vs. $7.1{\pm}2.1{\mu}mol$/L) or incidence of the MTHFR genotype variant (CC, 35% vs. 33%; CT, 40% vs. 53%; and TT, 25% vs. 14%). In the RM group, individuals with the TT variant ($7.7{\pm}1.1{\mu}mol$/L) had higher homocysteine levels than those with the CC and CT variants ($7.4{\pm}1.9{\mu}mol$/L and $7.4{\pm}1.2{\mu}mol$/L) and those with the CT variant ($19.2{\pm}8.1%$) had a higher proportion of CD3-/CD56+ pbNK cells than those with the CC and TT variants ($17.7{\pm}6.6%$ and $17.9{\pm}7.0%$), but the results of both comparisons were statistically insignificant. Conclusion: These preliminary results show no difference in plasma homocysteine levels between the RM and control groups or among MTHFR genotype variants in the RM group, which may suggest that the plasma homocysteine level is difficult to use as a predictive marker of RM in the Korean population. A study of a larger number of patients is needed.

Keywords

References

  1. Strobino B, Fox HE, Kline J, Stein Z, Susser M, Warburton D. Characteristics of women with recurrent spontaneous abortions and women with favorable reproductive histories. Am J Public Health 1986;76:986-91. https://doi.org/10.2105/AJPH.76.8.986
  2. Steegers-Theunissen RP, Boers GH, Blom HJ, Trijbels FJ, Eskes TK. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet 1992;339:1122-3.
  3. Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, et al. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 1993;60:820-5. https://doi.org/10.1016/S0015-0282(16)56282-7
  4. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a metaanalysis. Fertil Steril 2000;74:1196-9. https://doi.org/10.1016/S0015-0282(00)01595-8
  5. Nelen WL, Steegers EA, Eskes TK, Blom HJ. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 1997;350:861.
  6. Nelen WL, van der Molen EF, Blom HJ, Heil SG, Steegers EA, Eskes TK. Recurrent early pregnancy loss and genetic-related disturbances in folate and homocysteine metabolism. Br J Hosp Med 1997;58:511-3.
  7. 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;181:126-30. https://doi.org/10.1016/S0002-9378(99)70447-3
  8. Kumar KS, Govindaiah V, Naushad SE, Devi RR, Jyothy A. Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss. J Obstet Gynaecol 2003;23:55-8. https://doi.org/10.1080/0144361021000043263
  9. Greene ND, Dunlevy LE, Copp AJ. Homocysteine is embryotoxic but does not cause neural tube defects in mouse embryos. Anat Embryol (Berl) 2003;206:185-91. https://doi.org/10.1007/s00429-002-0284-3
  10. Durand P, Lussier-Cacan S, Blache D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J 1997;11:1157-68. https://doi.org/10.1096/fasebj.11.13.9367351
  11. Nishinaga M, Ozawa T, Shimada K. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 1993;92:1381-6. https://doi.org/10.1172/JCI116712
  12. Schroecksnadel K, Frick B, Wirleitner B, Schennach H, Fuchs D. Homocysteine accumulates in supernatants of stimulated human peripheral blood mononuclear cells. Clin Exp Immunol 2003;134:53-6. https://doi.org/10.1046/j.1365-2249.2003.02251.x
  13. Hague WM. Homocysteine and pregnancy. Best Pract Res Clin Obstet Gynaecol 2003;17:459-69. https://doi.org/10.1016/S1521-6934(03)00009-9
  14. Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997;95:1119-21. https://doi.org/10.1161/01.CIR.95.5.1119
  15. Widner B, Leblhuber F, Frick B, Laich A, Artner-Dworzak E, Fuchs D. Moderate hyperhomocysteinaemia and immune activation in Parkinson's disease. J Neural Transm 2002;109:1445-52. https://doi.org/10.1007/s00702-002-0758-8
  16. Steegers-Theunissen RP, Steegers EA, Thomas CM, Hollanders HM, Peereboom-Stegeman JH, Trijbels FJ, et al. Study on the presence of homocysteine in ovarian follicular fluid. Fertil Steril 1993;60:1006-10. https://doi.org/10.1016/S0015-0282(16)56401-2
  17. Kim IH, Van Langendonckt A, Van Soom A, Vanroose G, Casi AL, Hendriksen PJ, et al. Effect of exogenous glutathione on the in vitro fertilization of bovine oocytes. Theriogenology 1999;52:537-47. https://doi.org/10.1016/S0093-691X(99)00150-8
  18. Ali AA, Bilodeau JF, Sirard MA. Antioxidant requirements for bovine oocytes varies during in vitro maturation, fertilization and development. Theriogenology 2003;59:939-49. https://doi.org/10.1016/S0093-691X(02)01125-1
  19. Bedaiwy MA, Falcone T, Mohamed MS, Aleem AA, Sharma RK, Worley SE, et al. Differential growth of human embryos in vitro: role of reactive oxygen species. Fertil Steril 2004;82:593-600. https://doi.org/10.1016/j.fertnstert.2004.02.121
  20. Kwak JY, Beaman KD, Gilman-Sachs A, Ruiz JE, Schewitz D, Beer AE. Up-regulated expression of CD56+, CD56+/CD16+, and CD19+ cells in peripheral blood lymphocytes in pregnant women with recurrent pregnancy losses. Am J Reprod Immunol 1995;34:93-9. https://doi.org/10.1111/j.1600-0897.1995.tb00924.x
  21. Kwak JY, Kwak FM, Ainbinder SW, Ruiz AM, Beer AE. Elevated peripheral blood natural killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions. Am J Reprod Immunol 1996;35:363-9. https://doi.org/10.1111/j.1600-0897.1996.tb00495.x
  22. Emmer PM, Nelen WL, Steegers EA, Hendriks JC, Veerhoek M, Joosten I. Peripheral natural killer cytotoxicity and CD56(pos) CD16(pos) cells increase during early pregnancy in women with a history of recurrent spontaneous abortion. Hum Reprod 2000;15:1163-9. https://doi.org/10.1093/humrep/15.5.1163
  23. Frick B, Rudzite V, Schröcksnadel K, Kalnins U, Erglis A, Trusinskis K, et al. Coincidental increase of homocysteine and neopterin in patients with coronary heart disease. Pteridines 2003;14:43-8.
  24. Schroecksnadel K, Frick B, Kaser S, Wirleitner B, Ledochowski M, Mur E, et al. Moderate hyperhomocysteinaemia and immune activation in patients with rheumatoid arthritis. Clin Chim Acta 2003;338:157-64. https://doi.org/10.1016/j.cccn.2003.09.003
  25. Su SJ, Huang LW, Pai LS, Liu HW, Chang KL. Homocysteine at pathophysiologic concentrations activates human monocyte and induces cytokine expression and inhibits macrophage migration inhibitory factor expression. Nutrition 2005;21:994-1002. https://doi.org/10.1016/j.nut.2005.01.011
  26. Tso TK, Huang WN, Huang HY, Chang CK. Relationship of plasma interleukin-18 concentrations to traditional and non-traditional cardiovascular risk factors in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2006;45:1148-53. https://doi.org/10.1093/rheumatology/kel082
  27. Lazzerini PE, Selvi E, Lorenzini S, Capecchi PL, Ghittoni R, Bisogno S, et al. Homocysteine enhances cytokine production in cultured synoviocytes from rheumatoid arthritis patients. Clin Exp Rheumatol 2006;24:387-93.
  28. Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril 2006;86:1716-22. https://doi.org/10.1016/j.fertnstert.2006.05.052

Cited by

  1. Significant Impact of the MTHFR Polymorphisms and Haplotypes on Male Infertility Risk vol.8, pp.7, 2011, https://doi.org/10.1371/journal.pone.0069180
  2. The PAI‐1 4G/5G and ACE I/D Polymorphisms and Risk of Recurrent Pregnancy Loss: A Case–Control Study vol.72, pp.6, 2011, https://doi.org/10.1111/aji.12302
  3. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation vol.293, pp.6, 2011, https://doi.org/10.1007/s00404-015-3944-2
  4. MTHFR 3'-untranslated region polymorphisms contribute to recurrent pregnancy loss risk and alterations in peripheral natural killer cell proportions vol.44, pp.3, 2017, https://doi.org/10.5653/cerm.2017.44.3.152
  5. Methylenetetrahydrofolate Reductase Polymorphisms and Risk of Recurrent Pregnancy Loss: a Case-Control Study vol.32, pp.12, 2011, https://doi.org/10.3346/jkms.2017.32.12.2029
  6. Prolactin receptor gene polymorphism and the risk of recurrent pregnancy loss: a case-control study vol.38, pp.2, 2011, https://doi.org/10.1080/01443615.2017.1351932
  7. 3′-UTR Polymorphisms in the Vascular Endothelial Growth Factor Gene (VEGF) Contribute to Susceptibility to Recurrent Pregnancy Loss (RPL) vol.20, pp.13, 2011, https://doi.org/10.3390/ijms20133319
  8. Inherited thrombophilia and anticoagulant therapy for women with reproductive failure vol.85, pp.4, 2011, https://doi.org/10.1111/aji.13378