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

Charlotte A. Hobbs, Mario A. Cleves, Stewart L. Macleod, Stephen W. Erickson, Xinyu Tang, Jingyun Li, Ming Li, Todd Nick, Sadia Malik

Research output: Contribution to journalArticle

20 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)116-126
Number of pages11
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume100
Issue number2
DOIs
StatePublished - Feb 1 2014

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Homocysteine
Folic Acid
Single Nucleotide Polymorphism
Mothers
Genes
Glutamate-Cysteine Ligase
Thymidylate Synthase
Gene-Environment Interaction
Catalytic Domain

Keywords

  • Conotruncal heart defects
  • Folic acid
  • Gene X environment interaction
  • Genetics
  • Oxidative stress
  • Single nucleotide polymorphisms

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Developmental Biology

Cite this

Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways. / Hobbs, Charlotte A.; Cleves, Mario A.; Macleod, Stewart L.; Erickson, Stephen W.; Tang, Xinyu; Li, Jingyun; Li, Ming; Nick, Todd; Malik, Sadia.

In: Birth Defects Research Part A - Clinical and Molecular Teratology, Vol. 100, No. 2, 01.02.2014, p. 116-126.

Research output: Contribution to journalArticle

Hobbs, Charlotte A. ; Cleves, Mario A. ; Macleod, Stewart L. ; Erickson, Stephen W. ; Tang, Xinyu ; Li, Jingyun ; Li, Ming ; Nick, Todd ; Malik, Sadia. / Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways. In: Birth Defects Research Part A - Clinical and Molecular Teratology. 2014 ; Vol. 100, No. 2. pp. 116-126.
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AU - Erickson, Stephen W.

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AB - 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.

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