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

Ital J Pediatr. 2019 Mar 14;45(1):37. doi: 10.1186/s13052-019-0630-1.

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.

Keywords: Gene; Neural tube defects; One-carbon metabolism; Polymorphism.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Carbon / metabolism
  • Case-Control Studies
  • Chi-Square Distribution
  • China
  • Female
  • Ferredoxin-NADP Reductase / genetics
  • Folic Acid Deficiency / diagnosis
  • Folic Acid Deficiency / epidemiology
  • Folic Acid Deficiency / genetics*
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / epidemiology*
  • Genotype
  • Humans
  • Infant, Newborn
  • Logistic Models
  • Male
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Minor Histocompatibility Antigens / genetics
  • Neural Tube Defects / epidemiology
  • Neural Tube Defects / genetics*
  • Neural Tube Defects / physiopathology
  • Odds Ratio
  • Polymorphism, Single Nucleotide / genetics*
  • Pregnancy
  • Reference Values

Substances

  • Genetic Markers
  • Minor Histocompatibility Antigens
  • Carbon
  • methionine synthase reductase
  • Ferredoxin-NADP Reductase
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • MTHFD1 protein, human
  • Methylenetetrahydrofolate Dehydrogenase (NADP)