Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk

Mol Genet Metab. 2003 Jul;79(3):197-200. doi: 10.1016/s1096-7192(03)00086-6.


Genetic variants in folate metabolism have been reported to increase risk for neural tube defects (NTD). The first such sequence change was the 677C-->T substitution in methylenetetrahydrofolate reductase (MTHFR), but additional sequence changes have been identified in enzymes or transporters for folates. Two recently identified variants are the 1561C-->T (H475Y) mutation in glutamate carboxypeptidase II (GCPII) and the 80A-->G (H27R) change in the reduced folate carrier RFC-1. We examined a group of mothers of spina bifida offspring, and a group of control women, for the above polymorphisms to assess their impact on NTD risk as well as on homocysteine and nutrient (RBC folate, serum folate, and serum cobalamin) levels. The GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels; homozygous mutant (YY) women were not observed in our study group. The homozygous mutant (RR) genotype for the RFC-1 gene was not associated with a significant difference in NTD risk (OR=1.39, 95% CI=0.55-3.54), but there was a borderline significant (p=0.065) decrease in RBC folate levels, compared with the HH genotype. However, the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in NTD risk (OR=4.6, 95% CI=1.47-14.37). Since this small study is the first to demonstrate increased risk for women with the RFC-1 variant for having a child with a NTD, additional larger studies are required to confirm this change as another potential genetic modifier for spina bifida risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Canada
  • Carrier Proteins / genetics*
  • Female
  • Folic Acid / blood
  • Glutamate Carboxypeptidase II / genetics*
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Transport Proteins*
  • Mutation
  • Neural Tube Defects / genetics*
  • Polymorphism, Genetic / genetics*
  • Pregnancy
  • Risk Factors
  • Spinal Dysraphism / genetics*


  • Carrier Proteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • SLC19A2 protein, human
  • Folic Acid
  • Glutamate Carboxypeptidase II