Abstract P073: A Novel Epigenetic Link Between Gestational Diabetes Mellitus and Macrosomia

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<0.001). Anthropometric measurements of all enrolled women were completed as part of usual prenatal care; blood draws for DNA methylation analysis (using the Illumina 850K array) were collected from children (median age 5.9 years, range 3.1-10.0). We used logistic regression for all analyses and adjusted for maternal height, age, smoking status, pre-pregnancy overweight/obesity, weight gain during pregnancy, parity, and hypertensive disorders of pregnancy as well as child sex and gestational age at delivery. FDR adjustment was used to correct all candidate gene CpG analyses for multiple testing, with FDR-adjusted P<0.05 considered statistically significant.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:MESTis 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 MESTmay play an important role in the link between GDM and macrosomia.