Alterations in Metabolites Associated With Umbilical Cord Blood in Monozygotic Twins Discordant for Congenital Heart Disease

ABSTRACT The specific mechanisms and screening methods for congenital heart disease (CHD) remain elusive. Evidence indicates that aberrant maternal metabolomic profiles are associated with CHD, but it is uncertain whether such an association exists in umbilical cord blood. This study aimed to measure the metabolome shifts in monozygotic (MZ) twins discordant for CHD and, if present, identify the altered metabolites and metabolic pathways. Umbilical cord blood from three pairs of MZ twins discordant for CHD, identified through the prospective, population‐based longitudinal twin study (LoTiS), was subjected to ultrahigh‐performance liquid chromatography coupled with mass spectrometry (UHPLC‐MS/MS) based metabolomic analysis. Orthogonal partial least square‐discriminate analysis (OPLS‐DA) and random forest (RF) analysis were used to determine differences in metabolic profiles and individual metabolites. In univariate analysis, two specific metabolites were identified in the umbilical cord blood of CHD cases compared to their MZ twins without complications. After the paired‐sample t ‐test, four differentially expressed metabolites (DEMs) were identified, three of which were closely related to fatty acids and their metabolism. Enrichment pathway analysis revealed dysregulation of various metabolic pathways, including glucose metabolism, lipid metabolism, and amino acid metabolism pathways, in MZ twins with CHD compared to their healthy counterparts. The results demonstrated that the metabolomic signature of umbilical cord blood in CHD differs from that of their healthy MZ co‐twins, and the revelation of associated metabolites and pathways provide preliminary clues for generating hypotheses about the metabolic correlates of CHD predisposition. Findings are limited by small sample size and require validation in larger, independent cohorts.