Association between placental DNA methylation and fetal congenital heart disease

Abstract

Congenital heart disease (CHD) is a worldwide problem with high morbidity and mortality. Early diagnosis of congenital heart disease is still a challenge in clinical work. In recent years, few studies indicated that placental methylation may be predictors of CHD. More studies are needed to confirm the association between placental methylation and CHD. The aim of this study was to investigate the association between prenatal placental DNA methylation and CHD. Placental tissues were obtained from four fetuses during the second trimester with isolated, non-syndromic congenital heart disease, including three cases with double outlet right ventricle (DORV) and one case with tetralogy of Fallot (TOF), and four unaffected fetuses as controls. The Illumina Infinium Human Methylation 850K BeadChip assay was employed to identify differential methylation sites (DMSs) and differential methylation regions (DMRs). Differential methylation was evaluated by comparing the β-values for individual CpG loci in cases vs. controls. In addition, the function of genes was assessed through KEGG enrichment analysis, Gene Ontology (GO) analysis and KEGG pathway analysis. Compared with the control group, we identified 9625 differential methylation genes on 26,202 DMSs (p < 0.05), of which 6997 were hyper-methylation and 2628 were hypo-methylation. The top 30 terms of GO biological process and KEGG enrichment analysis of DMSs were connected with multiple important pathways of heart development and disease. Ten differentially methylated regions and the genes related to DMRs, such as TLL1, CRABP1, FDFT1, and PCK2, were identified. The deformity caused by the loss of function of these genes is remarkably consistent with the clinical phenotype of our cases. The DNA methylation level of placental tissue is closely associated with fetal congenital heart disease.

Keywords: Congenital heart disease; Differential methylation; Methylation; Placenta.