Child's Nervous System

, Volume 34, Issue 4, pp 725–729 | Cite as

Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China

  • Yulian Fang
  • Ruiping Zhang
  • Xiufang Zhi
  • Linsheng Zhao
  • Lirong Cao
  • Yizheng Wang
  • Chunquan Cai
Original Paper



Neural tube defects (NTDs) are one of the most prevalent and the most severe congenital malformations worldwide. Studies have confirmed that folic acid supplementation could effectively reduce NTDs risk, but the genetic mechanism remains unclear. In this study, we explored association of single nucleotide polymorphisms (SNP) within folate metabolic pathway genes with NTDs in Han population of Northern China.


We performed a case-control study to compare genotype and allele distributions of SNPs in 152 patients with NTDs and 169 controls. A total of 16 SNPs within five genes were genotyped by the Sequenom MassARRAY assay.


Our results indicated that three SNPs associated significantly with NTDs (P<0.05). For rs2236225 within MTHFD1, children with allele A or genotype AA had a high NTDs risk (OR=1.500, 95%CI=1.061~2.120; OR=2.862, 95%CI=1.022~8.015, respectively). For rs1801133 within MTHFR, NTDs risk markedly increased in patients with allele T or genotype TT (OR=1.552, 95%CI=1.130~2.131; OR=2.344, 95%CI=1.233~4.457, respectively). For rs1801394 within MTRR, children carrying allele G and genotype GG had a higher NTDs risk (OR=1.533, 95%CI=1.102~2.188; OR=2.355, 95%CI=1.044~5.312, respectively).


Our results suggest that rs2236225 of MTHFD1 gene, rs1801133 of MTHFR gene and rs1801394 of MTRR gene were associated with NTDs in Han population of Northern China.


Neural tube defects Polymorphisms Folate metabolism Susceptibility 



We are grateful to all the families for their NTDs-affected children enrolled in this study. We also extend our thanks to the staff of Tianjin Children’s Hospital for their cooperation and support in the collection of samples.

Funding information

This research was supported by the National 973 Program on Population and Health (no. 2013CB945404), the Natural Science Foundation of Tianjin City of China (no. 14JCYBJC25000), the Ministry of Science and Technology of P.R. China, and the Project of Tianjin Health Care Professionals (no. 15KR12), the Key Project of Tianjin Health Care Professionals (no.16KG166), and the National Natural Science of Foundation of China (no. 81770612).

Compliance with ethical standards

This study was approved by the Ethics Committee of Tianjin Children’s Hospital and written informed consent for the use of clinical data and blood samples was signed by all participants.

Conflict of interest

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


  1. 1.
    Greene ND, Stanier P, Copp AJ (2009) Genetics of human neural tube defects. Hum Mol Genet 18:R113–R129CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Copp AJ, Brook FA, Estibeiro JP, Shum AS, Cockroft DL (1990) The embryonic development of mammalian neural tube defects. Prog Neurobiol 35:363–403CrossRefPubMedGoogle Scholar
  3. 3.
    Molloy AM, Pangilinan F, Brody LC (2017) Genetic risk factors for folate-responsive neural tube defects. Annu Rev Nutr 37:269–291CrossRefPubMedGoogle Scholar
  4. 4.
    Au KS, Findley TO, Northrup H (2017) Finding the genetic mechanisms of folate deficiency and neural tube defects—leaving no stone unturned. Am J Med Genet A 173:3042–3057CrossRefPubMedGoogle Scholar
  5. 5.
    van der Linden IJ, Afman LA, Heil SG, Blom HJ (2006) Genetic variation in genes of folate metabolism and neural-tube defect risk. Proc Nutr Soc 65:204–215CrossRefPubMedGoogle Scholar
  6. 6.
    Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270:2693–2698CrossRefPubMedGoogle Scholar
  7. 7.
    Wang Y, Liu Y, Ji W, Qin H, Wu H, Xu D, Tukebai T, Wang Z (2015) Analysis of MTR and MTRR polymorphisms for neural tube defects risk association. Medicine (Baltimore) 94:e1367CrossRefGoogle Scholar
  8. 8.
    Yadav U, Kumar P, Yadav SK, Mishra OP, Rai V (2015) Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis. Metab Brain Dis 30:7–24CrossRefPubMedGoogle Scholar
  9. 9.
    Momb J, Appling DR (2014) Mitochondrial one-carbon metabolism and neural tube defects. Birth Defects Res A Clin Mol Teratol 100:576–583CrossRefPubMedGoogle Scholar
  10. 10.
    Field MS, Kamynina E, Stover PJ (2016) MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability. Biochimie 126:27–30CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Meng J, Han L, Zhuang B (2015) Association between MTHFD1 polymorphisms and neural tube defect susceptibility. J Neurol Sci 348:188–194CrossRefPubMedGoogle Scholar
  12. 12.
    Yan L, Zhao L, Long Y, Zou P, Ji G, Gu A, Zhao P (2012) Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studies. PLoS One 7:e41689CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yu Y, Wang F, Bao Y, Lu X, Quan L, Lu P (2014) Association between MTHFR gene polymorphism and NTDs in Chinese Han population. Int J Clin Exp Med 7:2901–2906PubMedPubMedCentralGoogle Scholar
  14. 14.
    Gonzalez-Herrera L, Garcia-Escalante G, Castillo-Zapata I, Canto-Herrera J, Ceballos-Quintal J, Pinto-Escalante D, Diaz-Rubio F, Del AR, Orozco-Orozco L (2002) Frequency of the thermolabile variant C677T in the MTHFR gene and lack of association with neural tube defects in the State of Yucatan, Mexico. Clin Genet 62:394–398CrossRefPubMedGoogle Scholar
  15. 15.
    Liu ZZ, Zhang JT, Liu D, Hao YH, Chang BM, Xie J, Li PZ (2013) Interaction between maternal 5,10-methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene variants to increase the risk of fetal neural tube defects in a Shanxi Han population. Chin Med J 126:865–869PubMedGoogle Scholar
  16. 16.
    Olteanu H, Banerjee R (2001) Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. J Biol Chem 276:35558–35563CrossRefPubMedGoogle Scholar
  17. 17.
    Ouyang S, Li Y, Liu Z, Chang H, Wu J (2013) Association between MTR A2756G and MTRR A66G polymorphisms and maternal risk for neural tube defects: a meta-analysis. Gene 515:308–312CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yulian Fang
    • 1
  • Ruiping Zhang
    • 2
  • Xiufang Zhi
    • 2
  • Linsheng Zhao
    • 3
  • Lirong Cao
    • 2
  • Yizheng Wang
    • 2
  • Chunquan Cai
    • 4
  1. 1.Institute of PediatricsTianjin Children’s HospitalTianjinChina
  2. 2.Graduate College of Tianjin Medical UniversityTianjinChina
  3. 3.Department of PathologyTianjin Children’s HospitalTianjinChina
  4. 4.Department of NeurosurgeryTianjin Children’s HospitalTianjinChina

Personalised recommendations