Skip to main content
SpringerLink
Log in

Genetic polymorphisms of the cobalamin transport system are associated with idiopathic recurrent implantation failure

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Vitamin B12 (cobalamin, Cbl) plays a role in the recycling of folate, which is important in pregnancy. Transcobalamin II (TCN2) and transcobalamin receptor (TCblR) proteins are involved in the cellular uptake of Cbl. TCN2 binds Cbl in the plasma, and TCblR binds TCN2-Cbl at the cell surface. Therefore, we investigated the potential association between polymorphisms in Cbl transport proteins, TCN2 and TCblR, and recurrent implantation failure (RIF) susceptibility.

Methods

The genotypes of TCN2 67A>G, TCN2 776C>G, and TCblR 1104C>T were determined for RIF patients and healthy controls using a polymerase chain reaction restriction fragment length polymorphism assay. Additionally, statistical analysis was performed to compare the genotype frequencies between RIF patients and controls.

Results

The TCN2 67 polymorphism AG type was associated with RIF risk. Some allele combinations that contained the TCN2 67 polymorphism G allele were associated with increased RIF risk, whereas other allele combinations that contained the TCblR 1104 polymorphism T alleles were associated with decreased RIF risk. In genotype combination analysis, two combinations containing the TCN2 67 polymorphism AG type were associated with RIF risk.

Conclusion

Our study showed that the polymorphisms of TCN2 and TCblR are associated with RIF and are potential genetic predisposing factors for RIF among Korean women. Additionally, our findings support a potential role for TCN2 and TCblR in RIF among Korean women. However, further studies are required to investigate the role of the polymorphisms in those proteins and RIF because the roles of the TCN2 and TCblR polymorphisms in RIF are not clear.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rinehart J. Recurrent implantation failure: definition. J Assist Reprod Genet. 2007;24(7):284–7.

    Article  Google Scholar 

  2. Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine-Fenning NJ. What exactly do we mean by ‘recurrent implantation failure’? A systematic review and opinion. Reprod BioMed Online. 2014;28(4):409–23.

    Article  Google Scholar 

  3. Laufer N, Simon A. Recurrent implantation failure: current update and clinical approach to an ongoing challenge. Fertil Steril. 2012;97(5):1019–20.

    Article  Google Scholar 

  4. Simon A, Laufer N. Repeated implantation failure: clinical approach. Fertil Steril. 2012;97(5):1039–43.

    Article  Google Scholar 

  5. Quadros EV, Sequeira JM. Cellular uptake of cobalamin: transcobalamin and the TCblR/CD320 receptor. Biochimie. 2013;95(5):1008–18.

    Article  CAS  Google Scholar 

  6. Antony AC. In utero physiology: role of folic acid in nutrient delivery and fetal development. Am J Clin Nutr. 2007;85(2):598S–603S.

    Article  CAS  Google Scholar 

  7. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000;71(5):1295S–303S.

    Article  CAS  Google Scholar 

  8. Murto T, Svanberg AS, Yngve A, Nilsson TK, Altmäe S, Wånggren K, et al. Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility. Reprod BioMed Online. 2014;28(6):766–72.

    Article  CAS  Google Scholar 

  9. Teplitsky V, Huminer D, Zoldan J, Pitlik S, Shohat M, Mittelman M. Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults. Isr Med Assoc J. 2003;5(12):868–72.

    PubMed  Google Scholar 

  10. Zetterberg H, Regland B, Palmer M, Rymo L, Zafiropoulos A, Arvanitis D, et al. The transcobalamin codon 259 polymorphism influences the risk of human spontaneous abortion. Hum Reprod. 2002;17(12):3033–6.

    Article  CAS  Google Scholar 

  11. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J. 1993;7(14):1344–53.

    Article  CAS  Google Scholar 

  12. Namour F, Olivier J-L, Abdelmouttaleb I, Adjalla C, Debard R, Salvat C, et al. Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood. Blood. 2001;97(4):1092–8.

    Article  CAS  Google Scholar 

  13. Steegers-theunissen RP, Boers GH, Trijbels FJ, Eskes TK. Neural-tube defects and derangement of homocysteine metabolism. N Engl J Med. 1991;324(3):199–200.

    Article  CAS  Google Scholar 

  14. Mills JL, Lee Y, Conley M, Kirke P, McPartlin J, Weir DG, et al. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet. 1995;345(8943):149–51.

    Article  CAS  Google Scholar 

  15. 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(5):820–5.

    Article  CAS  Google Scholar 

  16. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril. 2000;74(6):1196–9.

    Article  CAS  Google Scholar 

  17. Obeid R, Herrmann W. Homocysteine, folic acid and vitamin B12 in relation to pre-and postnatal health aspects. Clin Chem Lab Med. 2005;43(10):1052–7.

    Article  CAS  Google Scholar 

  18. van der Put NM, Blom HJ. Neural tube defects and a disturbed folate dependent homocysteine metabolism. Eur J Obstet Gynecol Reprod Biol. 2000;92(1):57–61.

    Article  Google Scholar 

  19. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, et al. The natural history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet. 1985;37(1):1.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Baker H, DeAngelis B, Holland B, Gittens-Williams L, Barrett T Jr. Vitamin profile of 563 gravidas during trimesters of pregnancy. J Am Coll Nutr. 2002;21(1):33–7.

    Article  CAS  Google Scholar 

  21. Hall C. Transcobalamins I and II as natural transport proteins of vitamin B12. J Clin Invest. 1975;56(5):1125–31.

    Article  CAS  Google Scholar 

  22. Green R, Allen LH, Bjørke-Monsen A-L, Brito A, Guéant J-L, Miller JW, et al. Vitamin B 12 deficiency. Nat Rev Dis Primers. 2017;3:17040.

    Article  Google Scholar 

  23. Mills JL, Carter TC, Kay DM, Browne ML, Brody LC, Liu A, et al. Folate and vitamin B12-related genes and risk for omphalocele. Hum Genet. 2012;131(5):739–46.

    Article  CAS  Google Scholar 

  24. Cascalheira JF, Gonçalves M, Barroso M, Castro R, Palmeira M, Serpa A, et al. Association of the transcobalamin II gene 776C→ G polymorphism with Alzheimer’s type dementia: dependence on the 5, 10-methylenetetrahydrofolate reductase 1298A→ C polymorphism genotype. Ann Clin Biochem. 2015;52(4):448–55.

    Article  CAS  Google Scholar 

  25. Hsu F-C, Sides E, Mychaleckyj J, Worrall B, Elias G, Liu Y, et al. Transcobalamin 2 variant associated with poststroke homocysteine modifies recurrent stroke risk. Neurology. 2011;77(16):1543–50.

    Article  Google Scholar 

  26. Wang H, Wu S, Wu J, Sun S, Wu S, Bao W. Association analysis of the SNP (rs345476947) in the FUT2 gene with the production and reproductive traits in pigs. Genes Genomics. 2018;40(2):199–206.

    Article  CAS  Google Scholar 

  27. Timeva T, Shterev A, Kyurkchiev S. Recurrent implantation failure: the role of the endometrium. J Reprod Infertil. 2014;15(4):173–83.

    PubMed  PubMed Central  Google Scholar 

  28. Benkhalifa M, Demirol A, Sari T, Balashova E, Tsouroupaki M, Giakoumakis Y, et al. Autologous embryo–cumulus cells co-culture and blastocyst transfer in repeated implantation failures: a collaborative prospective randomized study. Zygote. 2012;20(2):173–80.

    Article  CAS  Google Scholar 

  29. D'Uva M, Di Micco P, Strina I, Alviggi C, Iannuzzo M, Ranieri A, et al. Hyperhomocysteinemia in women with unexplained sterility or recurrent early pregnancy loss from southern Italy: a preliminary report. Thromb J. 2007;5(1):10.

    Article  Google Scholar 

  30. Verhoef P, Stampfer MJ, Buring JF, Gaziano JM, Allen RH, Stabler SP, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. 1996;143(9):845–59.

    Article  CAS  Google Scholar 

  31. Hankey GJ, Eikelboom JW. Homocysteine and stroke. Curr Opin Neurol. 2001;14(1):95–102.

    Article  CAS  Google Scholar 

  32. Israelsson B, Brattström LE, Hultberg BL. Homocysteine and myocardial infarction. Atherosclerosis. 1988;71(2–3):227–33.

    Article  CAS  Google Scholar 

  33. Zetterberg H. Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications. Reprod Biol Endocrinol. 2004;2(1):7.

    Article  Google Scholar 

  34. Bellver J, Soares SR, Alvarez C, Munoz E, Ramírez A, Rubio C, et al. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod. 2007;23(2):278–84.

    Article  Google Scholar 

  35. Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011;34(1):75–81.

    Article  CAS  Google Scholar 

  36. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5(11):949–60.

    Article  CAS  Google Scholar 

  37. Shaw GM, O'Malley CD, Wasserman CR, Tolarova MM, Lammer EJ. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet A. 1995;59(4):536–45.

    Article  CAS  Google Scholar 

  38. Harris MJ. Insights into prevention of human neural tube defects by folic acid arising from consideration of mouse mutants. Birth Defects Res A Clin Mol Teratol. 2009;85(4):331–9.

    Article  CAS  Google Scholar 

  39. İpçİoğlu OM, Gueltepe M, Özcan Ö. Cobalamin deficiency during pregnancy expressed as elevated urine methylmalonic acid levels determined by a photometric assay. Turk J Med Sci. 2007;37(3):139–43.

    Google Scholar 

  40. Garcia MM, Guéant-Rodriguez RM, Pooya S, Brachet P, Alberto JM, Jeannesson E, et al. Methyl donor deficiency induces cardiomyopathy through altered methylation/acetylation of PGC-1α by PRMT1 and SIRT1. J Pathol. 2011;225(3):324–35.

    Article  CAS  Google Scholar 

  41. Castellanos-Sinco H, Ramos-Peñafiel C, Santoyo-Sánchez A, Collazo-Jaloma J, Martínez-Murillo C, Montaño-Figueroa E, et al. Megaloblastic anaemia: folic acid and vitamin B12 metabolism. Rev Med Hosp Gen (Mexico City). 2015;78(3):135–43.

    Google Scholar 

  42. Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25(1):27–42.

    Article  CAS  Google Scholar 

  43. Yi P, Melnyk S, Pogribna M, Pogribny IP, Hine RJ, James SJ. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem. 2000;275(38):29318–23.

    Article  CAS  Google Scholar 

  44. Cui S, Li W, Lv X, Wang P, Gao Y, Huang G. Folic acid supplementation delays atherosclerotic lesion development by modulating MCP1 and VEGF DNA methylation levels in vivo and in vitro. Int J Mol Sci. 2017;18(5):990.

    Article  Google Scholar 

  45. Steegers-Theunissen RP, Wathen NC, Eskes TK, Raaij-Selten B, Chard T. Maternal and fetal levels of methionine and homocysteine in early human pregnancy. BJOG. 1997;104(1):20–4.

    Article  CAS  Google Scholar 

  46. King JC. The risk of maternal nutritional depletion and poor outcomes increases in early or closely spaced pregnancies. J Nutr. 2003;133(5):1732S–6S.

    Article  CAS  Google Scholar 

  47. Bhat DS, Gruca LL, Bennett CD, Katre P, Kurpad AV, Yajnik CS, et al. Evaluation of tracer labelled methionine load test in vitamin B-12 deficient adolescent women. PLoS One. 2018;13(5):e0196970.

    Article  Google Scholar 

  48. Stanisławska-Sachadyn A, Woodside J, Sayers C, Yarnell J, Young I, Evans A, et al. The transcobalamin (TCN2) 776C> G polymorphism affects homocysteine concentrations among subjects with low vitamin B 12 status. Eur J Clin Nutr. 2010;64(11):1338–43.

    Article  Google Scholar 

  49. Kim HS, Lee BE, Jeon YJ, Rah H, Lee WS, Shin JE, et al. Transcobalamin II (TCN2 67A> G and TCN2 776C> G) and transcobalamin II receptor (TCblR 1104C> T) polymorphisms in Korean patients with idiopathic recurrent spontaneous abortion. Am J Reprod Immunol. 2014;72(3):337–46.

    Article  CAS  Google Scholar 

  50. Zetterberg H, Zafiropoulos A, Spandidos DA, Rymo L, Blennow K. Gene–gene interaction between fetal MTHFR 677C> T and transcobalamin 776C> G polymorphisms in human spontaneous abortion. Hum Reprod. 2003;18(9):1948–50.

    Article  CAS  Google Scholar 

  51. Yuan X, Yin P, Hao Q, Yan C, Wang J, Yan N. Single amino acid alteration between valine and isoleucine determines the distinct pyrabactin selectivity by PYL1 and PYL2. J Biol Chem. 2010;285(37):28953–8.

    Article  CAS  Google Scholar 

  52. Riedel BM, Molloy AM, Meyer K, Fredriksen Å, Ulvik A, Schneede J, et al. Transcobalamin polymorphism 67A-> G, but not 776C-> G, affects serum holotranscobalamin in a cohort of healthy middle-aged men and women. J Nutr. 2011;141(10):1784–90.

    Article  CAS  Google Scholar 

Download references

Funding

This study was partially supported by the National Research Foundation of Korea Grants funded by the Korean Government (2017R1D1A1B03031542, 2018R1D1A1B07044096, 2018R1D1A1A09082764) and by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI18C19990200).

Author information

Authors and Affiliations

  1. Department of Biomedical Science, College of Life Science, CHA University, 355, Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea

    Han Sung Park, Jung Oh Kim, Hui Jeong An, Chang Soo Ryu, Eun Ju Ko & Nam Keun Kim

  2. Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, 11, Yatap-ro 65beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea

    Young Ran Kim, Eun Hee Ahn & Ji Hyang Kim

  3. Fertility Center of CHA Gangnam Medical Center, CHA University, 566, Nonhyeon-ro, Gangnam-gu, Seoul, 06135, Republic of Korea

    Woo Sik Lee

Authors
  1. Han Sung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jung Oh Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Jeong An
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chang Soo Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eun Ju Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Young Ran Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eun Hee Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Woo Sik Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ji Hyang Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nam Keun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ji Hyang Kim or Nam Keun Kim.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of The Institutional Review Board of CHA Bundang Medical Center (Seongnam, South Korea) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

The PCR primer sequence and enzyme used for SNP genotyping (DOCX 25 kb)

ESM 2

Statistical power of genetic associations in the present case-control study (DOCX 33 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, H.S., Kim, J.O., An, H.J. et al. Genetic polymorphisms of the cobalamin transport system are associated with idiopathic recurrent implantation failure. J Assist Reprod Genet 36, 1513–1522 (2019). https://doi.org/10.1007/s10815-019-01455-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-019-01455-4

Keywords

Search

Navigation