Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida

Am J Med Genet. 2002 Feb 15;108(1):1-6. doi: 10.1002/ajmg.10195.


Women who consume folic acid in early pregnancy reduced their risks for delivering offspring with neural tube defects (NTDs). The underlying process by which folic acid facilitated this risk reduction is unknown. Investigating genetic variation that influences cellular absorption, transport, and metabolism of folate will help fill this data gap. We focused our studies on a candidate gene that is involved in folate transport, the reduced folate carrier 1 (RFC1). Using data from a California population-based case control interview study (1989-1991 birth cohorts), we investigated whether spina bifida risk was influenced by an interaction between a polymorphism of infant RFC1 at nucleotide 80 (A80G) and maternal periconceptional use of vitamins containing folic acid. Allelic variants of RFC1 were determined by genotyping 133 live-born spina bifida case infants and 188 control infants. The percentages of case infants with the A80/A80, G80/G80, and G80/A80 genotypes were 27.2%, 28.0%, and 44.7%, respectively. The percentages of control infants were similar: 26.1%, 29.3%, and 44.7%. Odds ratios of 1.0 (95% confidence interval 0.5-2.0) for the G80/G80 genotype and 1.1 (0.6-2.0) for the G80/A80 genotype were observed relative to the A80/A80 genotype. Among mothers who did not use vitamins, spina bifida risk was 2.4 (0.8-6.9) for infants with genotype G80/G80 compared to those with A80/A80 genotype. Among mothers who did use vitamins, the risk was 0.5 (0.1-3.1) for infants with the G80/G80 genotype. Although this study did not find an increased spina bifida risk for infants who were heterozygous or homozygous for RFC1 A80G, it did reveal modest evidence for a gene-nutrient interaction between infant homozygosity for the RFC1 G80/G80 genotype and maternal periconceptional intake of vitamins containing folic acid on the risk of spina bifida.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Biological Transport
  • Carrier Proteins / genetics*
  • Carrier Proteins / physiology
  • Case-Control Studies
  • Female
  • Folic Acid / metabolism
  • Folic Acid / therapeutic use*
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Infant, Newborn
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Membrane Transport Proteins*
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Mutation, Missense
  • Oxidoreductases Acting on CH-NH Group Donors / genetics
  • Oxidoreductases Acting on CH-NH Group Donors / physiology
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Spinal Dysraphism / genetics*
  • Spinal Dysraphism / prevention & control


  • Carrier Proteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • SLC19A2 protein, human
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)