Prenatal gestational diabetes mellitus exposure and accelerated offspring DNA methylation age in early childhood

Background: We investigated the association between prenatal GDM exposure and offspring DNA methylation (DNAm) age at 3-10 years of age in the Tianjin GDM Observational Study. Methods: This study included 578 GDM and 578 non-GDM mother-child pairs. Children underwent a physical exam that included anthropometric measurements and a blood draw for DNAm analysis (Illumina 850K array) at a median age of 5.9 years (range 3.1-10.2). DNAm age was calculated using two epigenetic clock algorithms (Horvath and Hannum). The residual resulting from regressing DNAm age on chronological age was used as a metric for age acceleration. Results: Chronological age was positively correlated with Horvath DNAm age (r=0.53,p<0.0001) and Hannum DNAm age (r=0.38,p<0.0001). Offspring age acceleration was higher in the GDM group than the non-GDM group after adjustment for potential confounders (Horvath: 4.96 months higher, adjusted for sex, pre-pregnancy BMI, cell-type proportions, and technical bias,p=0.0002; Hannum: 11.2 months higher, adjusted for cell-type proportions and technical bias,p<0.0001). Adjusted for age, sex, and pre-pregnancy BMI, increased offspring DNAm age acceleration by both methods was associated with increased offspring weight-for-age Z-score, BMI-for-age-Z-score, waist circumference, body fat percentage, subscapular skinfold, suprailiac skinfold, upper-arm circumference, and blood pressure; findings were stronger in the GDM group. Conclusions: We found that offspring of women with GDM exhibit accelerated epigenetic age compared to control participants, independent of other maternal factors. Epigenetic age in offspring was also associated with cardiometabolic risk factors, suggesting that GDM and GDM-associated factors may have long-term effects on offspring epigenetic age and contribute to health outcomes.