DNA Methylation Variation Is Identified in Monozygotic Twins Discordant for Congenital Heart Diseases

Aims:Multiple genes and environmental factors are known to be involved in congenital heart disease(CHD),but epigenetic variation has received little attention.Monozygotic(MZ)twins with CHD provide a unique model for exploring this phenomenon.In order to investigate the potential role of Deoxyribonucleic Acid(DNA)methyla-tion in CHD pathogenesis,the present study examined DNA methylation variation in MZ twins discordant for CHD,especially ventricular septal defect(VSD).Methods and Results:Using genome-wide DNA methylation profiles,we identified 4004 differentially methylated regions(DMRs)in 18 MZ twin pairs discordant for CHD,and 2826 genes were identified.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis revealed a list of CHD-associated pathways.To further investigate the role of DNA methylation in VSD,data from 7 pairs of MZ twins with VSD were analyzed.We identified 1614 DMRs corresponding to 1443 genes associated with arrhythmogenic right ventricular cardiomyopathy,cyclic guanosine monopho-sphate-protein kinase G(cGMP-PKG)signaling pathway by KEGG analysis,and cell-cell adhesion,calcium ion transmembrane transport by GO analysis.A proportion of DMR-associated genes were involved in calcium signaling pathways.The methylation changes of calcium signaling genes might be related to VSD pathogenesis.Conclusion:CHD is associated with differential DNA methylation in MZ twins.CHD may be etiologically linked to DNA methylation,and methylation of calcium signaling genes may be involved in the development of VSD.