title: Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas.
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Hobbs
authors.forename: Mario A
authors.initials: MA
authors.lastname: Cleves
authors.forename: Stewart L
authors.initials: SL
authors.lastname: Macleod
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Erickson
authors.forename: Xinyu
authors.initials: X
authors.lastname: Tang
authors.forename: Jingyun
authors.initials: J
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Todd
authors.initials: T
authors.lastname: Nick
authors.forename: Sadia
authors.initials: S
authors.lastname: Malik
mesh_terms: D000328:Adult; D001499:Bayes Theorem; D016022:Case-Control Studies; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000235:genetics* / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011446:Prospective Studies; D012307:Risk Factors; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism
chemical_list: D006710:Homocysteine; D005492:Folic Acid; D013940:Thymidylate Synthase; C546365:GCLM protein, human; D005721:Glutamate-Cysteine Ligase
keywords: conotruncal heart defects; folic acid; gene X environment interaction; genetics; oxidative stress; single nucleotide polymorphisms