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 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 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. Results 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. 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.

A spectrum project: preterm birth and small-for-gestational age among infants with birth defects

“…[27][28][29] Micronutrients may also have a role in the complex relationship between the development of a BD and intrauterine growth. Maternal folate metabolism is associated with neural tube, cardiac and limb defects, [30][31][32][33][34] and at least in some studies, with prematurity 3,21 and low birth weight. 11,24 Other micronutrients, including thiamin, riboflavin, vitamin A, vitamin E and zinc, have been implicated in both the risk of preterm delivery and BDs.…”

Low nourishment of B-vitamins is associated with hyperhomocysteinemia and oxidative stress in newly diagnosed cardiac patients

“…18 Folate deficiency is considered as the most common cause of hyperhomocysteinemia, and there is an increasing demand for the diagnosis and treatment of elevated serum HCY level in high-risk individuals in general and patients with manifest vascular disease in particular. 19 Our study has addressed the preventable risk factors associated with CVDs, using biochemical and nutritional approaches. Inadequate dietary intake of folate, vitamins B 6 , and B 12 has been associated with hyperhomocysteinemia based on their biochemical role as cofactors for enzymes mediated trans-methylation and transsulfuration pathways of HCY.…”

SNPMClust: Bivariate Gaussian Genotype Clustering and Calling for Illumina Microarrays

“…It builds on mclust (Fraley, Raftery, and Scrucca 2013;Fraley and Raftery 2002;Fraley, Raftery, Murphy, and Scrucca 2012), an R package for normal mixture modeling. SNPMClust (pronounced snip-em-clust) has been used in multiple studies at the Arkansas Center for Birth Defects Research and Prevention on the Illumina GoldenGate custom genotyping platform (Chowdhury et al 2012;Hobbs et al 2014;Li et al 2014a,b;Tang et al 2014Tang et al , 2015 and is available through the Comprehensive R Archive Network at https://CRAN.R-project.org/package= SNPMClust. After describing the package, we compare the performance of SNPMClust to that of GenCall, Illumina's proprietary algorithm (Illumina Inc. 2005), on a data set of 94 buccal (cheek swab) DNA samples which had undergone whole-genome amplification (WGA) before genotyping on a custom SNP panel using the GoldenGate platform, at 1064 SNPs for which the true genotype was known with high confidence.…”