Placental epigenetic marks related to gestational weight gain reveal potential genes associated with offspring obesity parameters

Objective Offspring exposed to gestational obesity have an increased risk for chronic diseases. Increasing evidence suggests that epigenetics may play a mechanistic role in metabolic programming. This study aimed to identify placental DNA methylation marks associated with gestational weight gain (GWG) and to study their association with offspring obesity parameters at school age. Methods A global methylation array was performed in 24 placentas from mothers with different degrees of GWG (screening sample). The methylation percentage of four cytosine‐guanine (CpG) sites and the relative expression of the respective annotated genes were studied in 90 additional placentas (validation sample). Associations of these epigenetic marks with clinical parameters in the offspring at 6 years of age were examined. Results The screening analysis identified 104 CpG sites (97 genes) associated with GWG. The validation analysis of four selected CpG sites (annotating for FRAT1, SNX5, and KCNK3 genes) showed that the upregulation of SNX5 methylation, the downregulation of FRAT1 methylation, and KCNK3 underexpression associated with an adverse metabolic phenotype in children of women with increased GWG. Conclusions These results suggest that placental regulation of FRAT1, SNX5, and KCNK3 relates to obesity parameters in offspring exposed to excessive GWG and thereby could condition the risk for future metabolic disorders. In women with excessive gestational weight gain, the upregulation of SNX5 methylation, the downregulation of FRAT1 methylation, and KCNK3 underexpression associates with increased obesity risk in the offspring at 6 years of age.