Maternal epigenetics and genetic factors in congenital heart defects

Multiple factors including genetic susceptibilities, epigenetic mechanisms, and maternal lifestyle factors are thought to contribute to the development of non-syndromic congenital heart defects (CHDs). The present studies were designed to determine whether maternal epigenetic and genetic alterations were associated with CHDs. I sought 1) to investigate the associations between maternal DNA methylation and CHD-affected pregnancies; 2) to identify metabolites in the homocysteine-methionine pathway that predict variability in DNA methylation and 3) to determine if common variants in genes encoding for critical enzymes involved in folate metabolism and DNA methylation were associated with certain metabolites and DNA methylation.;Using a case-control study design, 180 mothers whose pregnancies were affected by non-syndromic CHDs and 187 mothers with unaffected pregnancies were selected for DNA methylation and genetic analysis. Blood was collected from Arkansas National Birth Defects Research and Prevention Study (NBDPS) participants who delivered a singleton live birth with a non-syndromic CHD (cases) and from women who had a live birth without a major defect (controls). Genomic DNA was isolated from peripheral blood samples for DNA methylation and genetic analyses. Maternal DNA methylation was assessed using the long interspersed nucleotide element-1 (LINE-1) and Methylight methodology, gene-specific methylation was conducted via IlluminaRTM Infinium Methylation Technology, and global methylation was assayed by an immunosorbent assay. The relationships between DNA methylation and selected homocysteine-methionine pathway biomarkers were determined by regression analysis. Using the Illumina RTM GoldenGate Assay, haplotype tagging SNPs (htSNPs) were analyzed in genes directly involved in homocysteine metabolism. The data collected was then used to determine potential SNP-metabolite, and SNP-DNA methylation associations.;LINE-1 hypomethylation was observed in case mothers when compared to controls. Strong correlations between LINE-1 methylation and selected metabolites were not achieved. Associations between gene-specific DNA methylation and CHDs were identified. Validation of a recently released global methylation assay did not achieve desired results. Associations between SNPs and metabolites did not achieve statistical significance after adjustment for multiple comparisons. Taken together, the results of my studies support the hypothesis that alterations in maternal DNA methylation are associated with CHDs.