Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects

Am J Med Genet. 1999 May 21;84(2):151-7. doi: 10.1002/(sici)1096-8628(19990521)84:2<151::aid-ajmg12>;2-t.


Folic acid administration to women in the periconceptional period reduces the occurrence of neural tube defects (NTDs) in their offspring. A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), 677C-->T, is the first genetic risk factor for NTDs in man identified at the molecular level. The gene encoding another folate-dependent enzyme, methionine synthase (MTR), has recently been cloned and a common variant, 2756A-->G, has been identified. We assessed genotypes and folate status in 56 patients with spina bifida, 62 mothers of patients, 97 children without NTDs (controls), and 90 mothers of controls, to determine the impact of these factors on NTD risk. Twenty percent of cases and 18% of case mothers were homozygous for the MTHFR polymorphism, compared to 11% of controls and 11% of control mothers, indicating that the mutant genotype conferred an increased risk for NTDs. The risk was further increased if both mother and child had this genotype. The MTR polymorphism was associated with a decreased O.R. (O.R.); none of the cases and only 10% of controls were homozygous for this variant. Red blood cell (RBC) folate was lower in cases and in case mothers, compared to their respective controls. Having a RBC folate in the lowest quartile of the control distribution was associated with an O.R. of 2.56 (95% CI 1.28-5.13) for being a case and of 3.05 (95% CI 1.54-6.03) for being a case mother. The combination of homozygous mutant MTHFR genotype and RBC folate in the lowest quartile conferred an O.R. for being a NTD case of 13.43 (CI 2.49-72.33) and an O.R. for having a child with NTD of 3.28 (CI 0.84-12.85). We propose that the genetic-nutrient interaction--MTHFR polymorphism and low folate status--is associated with a greater risk for NTDs than either variable alone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics*
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Erythrocytes / metabolism*
  • Female
  • Folic Acid / blood*
  • Genotype
  • Homocysteine / blood
  • Humans
  • Infant
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Middle Aged
  • Neural Tube Defects / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Polymorphism, Genetic*
  • Polymorphism, Restriction Fragment Length
  • Prevalence
  • Risk*
  • Vitamin B 12 / blood


  • Homocysteine
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Vitamin B 12