Skip to main content
SpringerLink
Log in

Association of neural tube defects with gene polymorphisms in one-carbon metabolic pathway

  • Original Paper
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

Purpose

Neural tube defects (NTDs) are common congenital malformations. In this study, we aimed to explore the association between single nucleotide polymorphisms (SNPs) related to one-carbon metabolism (OCM) and NTDs in Han population of Northern China.

Methods

A case-control study was conducted in 152 children with NTDs and 169 controls. Twenty-nine SNPs in five genes were genotyped by Sequenom MassARRAY technology, and haplotype analysis was done by Haploview4.2 software.

Results

The allele frequency of rs3733890 in betaine-homocysteine methyltransferase (BHMT) gene was statistically different between NTDs and control groups (P = 0.041), and the children with A allele had higher risk for NTDs than G allele (OR = 1.408, 95%CI 1.013–1.956). In addition, there was a statistical difference in the allele and genotype frequencies of rs1051266 in reduced folate carrier1 (RFC1) gene between cases and controls (P = 0.013, 0.034), and the risk for NTDs was also higher in children with G allele and GG genotype, compared with A allele and AA genotype, respectively (OR = 1.492, 95%CI 1.089–2.044; OR = 2.020, 95%CI 1.081–3.780). The statistical significant difference was also found in allele frequency of rs1805087 in methionine synthetase (MTR) gene between cases and controls (P = 0.031), and the children with G allele were associated with an increased NTDs risk, compared with A allele (OR = 1.664, 95%CI 1.045–2.647). Meanwhile, haplotype analysis showed C-A-A-A haplotype of BHMT, and G-G-G-T haplotype of RFC1 was correlated with an increased risk of NTDs, but C-G-A-A haplotype of BHMT and G-G-C-A haplotype of MTR might decrease the risk of NTDs.

Conclusions

The BHMT gene rs3733890, RFC1 gene rs1051266 and MTR gene rs1805087 were associated with the occurrence of NTDs in Han population of Northern China. It was confirmed that the gene variation related to OCM was one of the susceptibility factors for NTDs.

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

Fig. 1

Similar content being viewed by others

References

  1. Copp AJ, Greene ND, Murdoch JN (2003) The genetic basis of mammalian neurulation. Nat Rev Genet 4(10):784–793. doi:10.1038/nrg1181

    Article  PubMed  Google Scholar 

  2. Zhang RP, Fang YL, Wu B, Chemban MN, Laakhey N, Cai CQ, Shi OY (2016) Gene-gene interaction between VANGL1, FZD3, and FZD6 correlated with neural tube defects in Han population of Northern China. Genet Mol Res 15(3):gmr.15039010. doi:10.4238/gmr.15039010

    Article  CAS  Google Scholar 

  3. Blom HJ, Smulders Y (2011) Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 34(1):75–81. doi:10.1007/s10545-010-9177-4

    Article  CAS  PubMed  Google Scholar 

  4. Cai C, Shi O, Wang B, Chang B, Yang R, Wang Y, Wang F, Shen C (2014) Association between VANGL1 gene polymorphisms and neural tube defects. Neuropediatrics 45(4):234–239. doi:10.1055/s-0033-1364103

    Article  CAS  PubMed  Google Scholar 

  5. Zhang T, Lou J, Zhong R, Wu J, Zou L, Sun Y, Lu X, Liu L, Miao X, Xiong G (2013) Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature. PLoS One 8(4):e59570. doi:10.1371/journal.pone.0059570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Beaudin AE, Stover PJ (2007) Folate-mediated one-carbon metabolism and neural tube defects: balancing genome synthesis and gene expression. Birth Defects Res C Embryo Today 81(3):183–203. doi:10.1002/bdrc.20100

    Article  CAS  PubMed  Google Scholar 

  7. Cai C, Shi O (2014) Genetic evidence in planar cell polarity signaling pathway in human neural tube defects. Front Med 8(1):68–78. doi:10.1007/s11684-014-0308-4

    Article  PubMed  Google Scholar 

  8. Shi OY, Yang HY, Shen YM, Sun W, Cai CY, Cai CQ (2014) Polymorphisms in FZD3 and FZD6 genes and risk of neural tube defects in a northern Han Chinese population. Neurol Sci 35(11):1701–1706. doi:10.1007/s10072-014-1815-4

    Article  PubMed  Google Scholar 

  9. Piao W, Guo J, Bao Y, Wang F, Zhang T, Huo J, Zhang K (2016) Analysis of polymorphisms of genes associated with folate-mediated one-carbon metabolism and neural tube defects in Chinese Han Population. Birth Defects Res A Clin Mol Teratol 106(4):232–239. doi:10.1002/bdra.23478

    Article  CAS  PubMed  Google Scholar 

  10. Fang Y, Ma S, Shi O, Zhang P, Cai C (2015) Association between maternal MTHFR C677T polymorphism and neural tube defects in offsprings: a meta-analysis. Tianjin Med J 43(5):552–558. doi:10.11958/j.issn.0253-9896.2015.05.028 [Chinese]

    Article  CAS  Google Scholar 

  11. Blom HJ, Shaw GM, den Heijer M, Finnell RH (2006) Neural tube defects and folate: case far from closed. Nat Rev Neurosci 7(9):724–731. doi:10.1038/nrn1986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dunlevy LP, Chitty LS, Burren KA, Doudney K, Stojilkovic-Mikic T, Stanier P, Scott R, Copp AJ, Greene ND (2007) Abnormal folate metabolism in foetuses affected by neural tube defects. Brain 130(Pt 4):1043–1049. doi:10.1093/brain/awm028

    Article  PubMed  Google Scholar 

  13. Bailey LB, Berry RJ (2005) Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr 81(5):1213S–1217S

    Article  CAS  PubMed  Google Scholar 

  14. Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH, Bassuk AG, Kessler JA, Reed MC, Nijhout HF, George TM, Enterline DS, Gilbert JR, Speer MC, the NTD Collaborative Group (2006) Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect 114(10):1547–1552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhu H, Curry S, Wen S, Wicker NJ, Shaw GM, Lammer EJ, Yang W, Jafarov T, Finnell RH (2005) Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts? Am J Med Genet A 135(3):274–277. doi:10.1002/ajmg.a.30739

    Article  PubMed  Google Scholar 

  16. De Marco P, Calevo MG, Moroni A, Merello E, Raso A, Finnell RH, Zhu H, Andreussi L, Cama A, Capra V (2003) Reduced folate carrier polymorphism (80A-->G) and neural tube defects. Eur J Hum Genet 11(3):245–252. doi:10.1038/sj. ejhg. 5200946

    Article  PubMed  Google Scholar 

  17. Pei L, Zhu H, Ren A, Li Z, Hao L, Finnell RH, Li Z (2005) Reduced folate carrier gene is a risk factor for neural tube defects in a Chinese population. Birth Defects Res A Clin Mol Teratol 73(6):430–433. doi:10.1002/bdra.20130

    Article  CAS  PubMed  Google Scholar 

  18. Gos M, Sliwerska E, Szpecht-Potocka A (2004) Mutation incidence in folate metabolism genes and regulatory genes in Polish families with neural tube defects. J Appl Genet 45(3):363–368

    PubMed  Google Scholar 

  19. De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Finnell RH, Zhu H, Andreussi L, Cama A, Capra V (2002) Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet 47(6):319–324. doi:10.1007/s100380200043

    Article  PubMed  Google Scholar 

  20. O’Leary VB, Mills JL, Pangilinan F, Kirke PN, Cox C, Conley M, Weiler A, Peng K, Shane B, Scott JM, Parle-McDermott A, Molloy AM, Brody LC, Members of the Birth Defects Research Group (2005) Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol Genet Metab 85(3): 220–227. doi: 10.1016/j.ymgme. 2005.02.003

  21. Li K, Wahlqvist ML, Li D (2016) Nutrition, one-carbon metabolism and neural tube defects: a review. Nutrients 8(11):E741. doi:10.3390/nu8110741

    Article  CAS  PubMed  Google Scholar 

  22. Sanders LM, Zeisel SH (2007) Choline: dietary requirements and role in brain development. Nutr Today 42(4):181–186. doi:10.1097/01.NT.0000286155.55343.fa

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to all the participants enrolled in this study. This study was supported by the National Key Basic Research Program of China (973 Program) (No. 2013CB945404); the Tianjin Research Program of Application Foundation and Advanced Technology (No. 14JCYBJC25000); the Key Project of Tianjin Health and Family Planning Commission Natural Science Foundation (No. 2015KRl2); the Key Project of Tianjin Health Care Professionals (No. 16KG166); and the National Natural Science Foundation of China (No. 81770612).

Author information

Author notes

  1. Lirong Cao, Yizheng Wang, and Ruiping Zhang contributed equally to this study.

Authors and Affiliations

  1. Graduate college of Tianjin Medical University, Heping District, Tianjin, 300070, China

    Lirong Cao, Yizheng Wang & Ruiping Zhang

  2. Department of surgery, Tianjin Children’s Hospital, Beichen District, Tianjin, 300134, China

    Liang Dong & Hualei Cui

  3. Institute of pediatric, Tianjin Children’s Hospital, Beichen District, Tianjin, 300134, China

    Yulian Fang

  4. Department of pathology, Tianjin Children’s Hospital, Beichen District, Tianjin, 300134, China

    Linsheng Zhao

  5. School of Basic Medical Sciences, Tianjin Medical University, Heping District, Tianjin, 300070, China

    Ouyan Shi

  6. Department of neurosurgery, Tianjin Children’s Hospital, Beichen District, Tianjin, 300134, China

    Chunquan Cai

Authors
  1. Lirong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yizheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruiping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hualei Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yulian Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Linsheng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ouyan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chunquan Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ouyan Shi or Chunquan Cai.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were approved by the Medical Ethics Committee of Tianjin Children’s Hospital.

Research involving human participants and animals

This article did not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Data availability

The datasets during and analyzed during the current study could be available from the corresponding author on reasonable request.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, L., Wang, Y., Zhang, R. et al. Association of neural tube defects with gene polymorphisms in one-carbon metabolic pathway. Childs Nerv Syst 34, 277–284 (2018). https://doi.org/10.1007/s00381-017-3558-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-017-3558-z

Keywords

Search

Navigation