Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways

Birth Defects Res A Clin Mol Teratol. 2014 Feb;100(2):116-26. doi: 10.1002/bdra.23225. Epub 2014 Feb 18.


Background: We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine, and transsulfuration pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs

Methods: Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2008. DNA samples from 616 case-parental triads affected by CTDs and 1645 control-parental triads were genotyped using an Illumina® Golden Gate custom SNP panel. A hybrid design analysis, optimizing data from case and control trios, was used to identify maternal and fetal SNPs associated with CTDs

Results: Among 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability of <0.8. Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the glutamate-cysteine ligase, catalytic subunit (GCLC) gene. Fetal SNPs with the lowest Bayesian false-discovery probability (rs2612101, rs2847607, rs2847326, rs2847324) were found within the thymidylate synthetase (TYMS) gene. Additional analyses indicated that the risk of CTDs associated with candidate SNPs was modified by periconceptional folic acid supplementation. Nineteen maternal and nine fetal SNPs had a Bayesian false-discovery probability <0.8 for gene-by-environment (G × E) interactions with maternal folic acid supplementation.

Conclusion: These results support previous studies suggesting that maternal and fetal SNPs within folate, homocysteine, and transsulfuration pathways are associated with CTD risk. Maternal use of supplements containing folic acid may modify the impact of SNPs on the developing heart.

Keywords: conotruncal heart defects; folic acid; gene X environment interaction; genetics; oxidative stress; single nucleotide polymorphisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bayes Theorem
  • Case-Control Studies
  • Dietary Supplements*
  • Female
  • Folic Acid / administration & dosage*
  • Folic Acid / metabolism
  • Glutamate-Cysteine Ligase / genetics*
  • Glutamate-Cysteine Ligase / metabolism
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / metabolism
  • Heart Defects, Congenital / prevention & control
  • Homocysteine / metabolism
  • Humans
  • Infant, Newborn
  • Polymorphism, Single Nucleotide*
  • Pregnancy
  • Prospective Studies
  • Risk Factors
  • Thymidylate Synthase / genetics*
  • Thymidylate Synthase / metabolism


  • Homocysteine
  • Folic Acid
  • Thymidylate Synthase
  • Glutamate-Cysteine Ligase
  • glutamate-cysteine ligase modifier subunit, human

Supplementary concepts

  • Conotruncal cardiac defects