Longitudinal Analysis of Placental IRS1 DNA Methylation and Childhood Obesity

Accumulating evidence suggests that the predisposition to metabolic diseases is established in utero through epigenomic modifications. However, it remains unclear whether childhood obesity results from preexisting epigenomic alterations or whether obesity itself induces changes in the epigenome. This study aimed to identify DNA methylation marks in the placenta associated with obesity-related outcomes in children at age 6 and to assess these marks in blood samples at age 6 and whether they correlate with obesity-related outcomes at that time. Using an epigenome-wide DNA methylation microarray on 24 placental samples, we identified differentially methylated CpGs (DMCs) associated with offspring BMI-SDS at 6 years. Individual DMCs were validated in 147 additional placental and leukocyte samples from children at 6 years of age. The methylation and/or gene expression of IRS1 in both placenta and offspring leukocytes were significantly associated with various metabolic risk parameters at age 6 (all p ≤ 0.05). Logistic regression models (LRM) and machine learning (ML) models indicated that IRS1 methylation in the placenta could strongly predict offspring obesity. Our results suggest that IRS1 may serve as a potential biomarker for the prediction of obesity and metabolic risk in children.