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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 an exam with anthropometric measurements and blood draw for DNAm analysis (Illumina 850 K 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 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). Increased offspring DNAm age acceleration 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 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.

Background: Gestational diabetes mellitus (GDM) is a known risk factor for macrosomia, with recent estimates suggesting that between 15-45% of newborns of mothers with GDM are macrosomic (vs. 12% in non-GDM mothers). This study’s objectives were to explore associations between both maternal GDM and children’s macrosomia and DNA methylation of eight genes selected based on a literature review of candidates potentially involved in GDM and obesogenic pathways ( IGF1 , IGF2 , H19 , ARHGRF11 , MEST , NR3C1 , Adiponectin , and RETN ). Methods: Data were taken from the Tianjin GDM Observational study, in the 4th-largest city in China; subjects were ages 24-49 and diagnosed with GDM between 2005-2009. Baseline surveys were completed from 2009-2011 for 580 enrolled women-child pairs; an additional 580 women-child pairs without GDM and frequency matched on child sex and birth date were enrolled. We examined 572 GDM cases vs. 573 non-GDM controls; of these 177 children were born with macrosomia (114 to women with GDM, p Results: After analysis of 345 CpGs in eight target genes, one CpG was associated with macrosomia (cg14428359) and one with GDM (cg19466922) at FDR < 0.05; both CpGs were located in the gene MEST (3’ and 5’ untranslated regions, respectively). One additional CpG site in the promoter region of MEST (cg05862114) was associated with both GDM and macrosomia before FDR adjustment. All three CpGs were hypomethylated in both children of GDM mothers and macrosomia cases. Conclusions: MEST is a paternally imprinted gene that is highly expressed in fetal and placental tissue, and believed to play an important role in fetal development. It has also been found to have elevated expression in adipose tissue; epigenetic regulation of MEST may play an important role in the link between GDM and macrosomia.