Conotruncal Heart Defects and Common Variants in Maternal and Fetal Genes in Folate, Homocysteine and Transsulfuration Pathways
Published Date:Feb 18 2014
Source:Birth Defects Res A Clin Mol Teratol. 100(2):116-126.
Corporate Authors:National Birth Defects Prevention Study
Conotruncal Heart Defects
Gene X Environment Interaction
Heart Defects, Congenital
Polymorphism, Single Nucleotide
Single Nucleotide Polymorphisms
Pubmed Central ID:PMC4118819
Funding:5R01HD039054-12/HD/NICHD NIH HHS/United States
5U01DD000491-05/DD/NCBDD CDC HHS/United States
R01 HD039054/HD/NICHD NIH HHS/United States
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 pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs.
Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2007. DNA samples from 616 case-parental triads affected by CTDs and 1,645 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.
Among 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability (BFDP) 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 BFDP (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 9 fetal SNPs had BFDP <0.8 for gene-by-environment (GxE) interactions with maternal folic acid supplementation.
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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