Top

Published in:

Open Access 01-12-2019 | Folic Acid | Research

Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway

Authors: Chun-Quan Cai, Yu-Lian Fang, Jian-Bo Shu, Lin-Sheng Zhao, Rui-Ping Zhang, Li-Rong Cao, Yi-Zheng Wang, Xiu-Fang Zhi, Hua-Lei Cui, Ou-Yan Shi, Wei Liu

Published in: Italian Journal of Pediatrics | Issue 1/2019

Abstract

Background

Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord invoked by the insufficient intake of folic acid in the early stages of pregnancy and have a complex etiology involving both genetic and environmental factors. So the study aimed to explore the association between alterations in maternal one-carbon metabolism and NTDs in the offspring.

Methods

We conducted a case-control study to get a deeper insight into this association, as well as into the role of genetic polymorphisms. Plasma concentrations of folate, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and genotypes and alleles distributions of 52 SNPs in 8 genes were compared for 61 women with NTDs-affected offspring and 61 women with healthy ones.

Results

There were significant differences between groups with regard to plasma folate, SAM, SAH and SAM/SAH levels. Logistic regression results revealed a significant association between maternal plasma folate level and risk of NTDs in the offspring. For MTHFD1 rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227–5.529; OR = 1.847, 95%CI: 1.047–3.259). For MTHFR rs1801133 polymorphism, mothers having TT and CT genotypes were more likely to affect NTDs in the offspring (OR = 4.105, 95%CI: 1.271–13.258; OR = 3.333, 95%CI: 1.068–10.400). Moreover, mothers carrying T allele had a higher risk of NTDs in the offspring (OR = 1.798, 95%CI: 1.070–3.021). For MTRR rs1801394 polymorphism, the frequency of G allele was significantly higher in cases than in controls (OR = 1.763, 95%CI: 1.023–3.036). Mothers with NTDs-affected children had higher AG genotype in RFC1 rs1051226 polymorphism than controls, manifesting an increased risk for NTDs (OR = 3.923, 95%CI: 1.361–11.308).

Conclusion

Folic acid deficiency, MTHFD1 rs2236225, MTHFR rs1801133, MTRR rs1801349 and RFC1 rs1051226 polymorphisms may be maternal risk factors of NTDs.

Ouyang S, Liu Z, Li Y, Ma F, Wu J. Cystathionine beta-synthase 844ins68 polymorphism is unrelated to susceptibility to neural tube defects. Gene. 2014;535:119–23.CrossRef

Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet. 2003;4:784–93.CrossRef

Frey L, Hauser WA. Epidemiology of neural tube defects. Epilepsia. 2003;44(Suppl 3):4–13.CrossRef

Li K, Wahlqvist ML, Li D. Nutrition, one-carbon metabolism and neural tube defects: a review. Nutrients. 2016;8:741.CrossRef

Anonymous. Prevention of neural tube defects: results of the Medical Research Council vitamin study; MRC vitamin study research group. Lancet. 1991;338(8760):131–7.CrossRef

Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. NEJM. 1992;327:1832–5.CrossRef

Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWRRecomm Rep. 1992;11:1–7.

Dunlevy LP, Chitty LS, Burren KA, Doudney K, Stojilkovic-Mikic T, Stanier P, et al. Abnormal folate metabolism in fetuses affected by neural tube defects. Brain. 130:1043–9.

Yang M, Li W, Wan Z, Du Y. Elevated homocysteine levels in mothers with neural tube defects: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2017;30:2051–7.CrossRef

10.

Zhang T, Lou J, Zhong R, Wu J, Zou L, Sun Y, et al. Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature. PLoS One. 2013;8:e59570.CrossRef

11.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.CrossRef

12.

Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4.CrossRef

13.

Cai C, Shi O. Genetic evidence in planar cell polarity signaling pathway in human neural tube defects. Front Med. 2014;8:68–78.CrossRef

14.

Cai C, Shi O, Wang B, Chang B, Yang R, Wang Y, et al. Association between VANGL1 gene polymorphisms and neural tube defects. Neuropeditrics. 2014;45:234–9.CrossRef

15.

Fang Y, Zhang R, Zhi X, Zhao L, Cao L, Wang Y, et al. Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of northern China. Childs Nerv Syst. 2018;34(4):725–9.CrossRef

16.

Fu Y, Wang LL, Yi D, Jin L, Liu J, Zhang Y, et al. Association between maternal single nucleotide polymorphisms in genes regulation glucose metabolism and risk for neural tube defects in offspring. Birth Defects Res A Clin Mol Teratol. 2015;103:471–8.CrossRef

17.

Preventive Services Task Force US, Bibbins-Domingo K, Grossman DC. Folic acid supplementation for the prevention of neural tube defects: US preventive services task force recommendation statement. JAMA. 2017;317(2):183–9.CrossRef

18.

Centers for Disease Control and Prevention. CDC grand rounds: additional opportunities to prevent neural tube defects with folic acid fortification. MMWR Morb Mortal Wkly Rep. 2010;59(31):980–4.

19.

Fischer M, Stronati M, Lanari M. Mediterranean diet, folic acid, and neural tube defects. Ital J Pediatr. 2017;43:74.CrossRef

20.

Mills JL. Strategies for preventing folate-related neural tube defects supplements, fortified foods, or both. JAMA. 2017;317(2):144–5.CrossRef

21.

Finnell RH, Spiegelstein O, Wlodarczyk B, Triplett A, Pogribny IP, Melnyk S, et al. DNA methylation in Folbp1 knockout mice supplemented with folic acid during gestation. J Nutr. 2002;132:2457S–61S.CrossRef

22.

Ehrlich M. Expression of various genes is controlled by DNA methylation during mammalian development. J Cell Biochem. 2003;88:899–910.CrossRef

23.

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;275:29318–23.CrossRef

24.

Parle-McDermott A, Kirke PN, Mills JL, Molloy AM, Cox C, O'Leary VB, et al. Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population. Eur J Hum Genet. 2006;14:768–72.CrossRef

25.

Carroll N, Pangilinan F, Molloy AM, Troendle J, Mills JL, Kirke PN, et al. Analysis of the MTHFD1 promoter and risk of neural tube defects. Hum Genet. 2009;125:247–56.CrossRef

26.

Liu Z, Zhang J, Liu D, Hao YH, Chang BM, Xie J, et al. 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. 2013;126:865–9.PubMed

27.

Lucock M, Daskalakis I, Briggs D, Yates Z, Leveve M. Altered folate metabolism and disposition in mothers affected by a spina bifida pregnancy: influence of 677c→ t methylenetetrahydrofolate reductase and 2756a→g methionine synthase genotypes. Mol Genet Metab. 2000;70:27–44.CrossRef

28.

Fang Y, Ma S, Shi O, Zhang P, Cai C. Association between maternal MTHFR C677T polymorphism and neural tube defects in offspring: a meta-analysis. Tianjin Med J. 2015;43:552–8.

29.

Ouyang S, Li Y, Liu Z, Chang H, Wu J. Association between MTR A2756G and MTRR A66G polymorphisms and maternal risk for neural tube defects: a meta-analysis. Gene. 2013;515:308–12.CrossRef

30.

Matherly LH, Goldman ID. Membrane transport of folate. Vitam Horm. 2003;66:403–56.CrossRef

31.

Cao L, Wang Y, Zhang R, Dong L, Cui H, Fang Y, et al. Association of neural tube defects with gene polymorphisms in one-carbon metabolic pathway. Childs Nerv Syst. 2018;34:277–84.CrossRef

32.

Shang Y, Zhao H, Niu B, Li WI, Zhou R, Zhang T, et al. Correlation of polymorphism of MTHFRs and RFC- 1 genes with neural tube defects in China. Birth Defects Res A Clin Mol Teratol. 2008;82:3–7.CrossRef

Title: Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway
Authors: Chun-Quan Cai
Yu-Lian Fang
Jian-Bo Shu
Lin-Sheng Zhao
Rui-Ping Zhang
Li-Rong Cao
Yi-Zheng Wang
Xiu-Fang Zhi
Hua-Lei Cui
Ou-Yan Shi
Wei Liu
Publication date: 01-12-2019
Publisher: BioMed Central
Keyword: Folic Acid
Published in: Italian Journal of Pediatrics / Issue 1/2019
Electronic ISSN: 1824-7288
DOI: https://doi.org/10.1186/s13052-019-0630-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2019

Proton therapy in the most common pediatric non-central nervous system malignancies: an overview of clinical and dosimetric outcomes

Efficacy of the gluten free diet in the management of functional gastrointestinal disorders: a systematic review on behalf of the Italian Society of Paediatrics

Antibiotic prescriptions in Italian hospitalised children after serial point prevalence surveys (or pointless prevalence surveys): has anything actually changed over the years?

Management of chronic urticaria in children: a clinical guideline

Clinical and genetic spectrum of interstitial lung disease in Chinese children associated with surfactant protein C mutations

Italian guidelines for the prevention and management of dental trauma in children