Fetal growth is determined by the feto-placental genome interacting with the maternal in utero environment. Failure of this interplay leads to poor placental development and fetal growth restriction (FGR), which is associated with future metabolic disease. We investigated whether whole genome methylation differences existed in umbilical cord blood and placenta, between gestational-matched, FGR, and appropriately grown (AGA) neonates. Using the Infinium HumanMethylation450 BeadChip®, we found that DNA from umbilical cord blood of FGR born at term (n = 19) had 839 differentially methylated positions (DMPs) that reached genome-wide significance compared with AGA (n = 18). Using gestational age as a continuous variable, we identified 76,249 DMPs in cord blood (adj. P < 0.05) of which 121 DMPs were common to the 839 DMPs and were still evident when comparing 12 FGR with 12 AGA [39.9 ± 1.2 vs. 40.0 ± 1.0 weeks (mean ± SD), respectively]. A total of 53 DMPs had a β methylation difference >10% and 25 genes were co-methylated more than twice within 1000 base pairs. Gene Ontology (GO) analysis of DMPs supported their involvement in gene regulation and transcription pathways related to organ development and metabolic function. A similar profile of DMPs was found across different cell types in the cord blood. At term, no DMPs between FGR and AGA placentae reached genome-wide significance, validated with an external dataset. GO analysis of 284 pre-term, placental DMPs associated with autophagy, oxidative stress and hormonal responses. Growth restricted neonates have distinct DNA methylation profiles in pre-term placenta and in cord blood at birth, which may predispose to future adult disease.
Keywords: AGA, appropriately grown offspring; BMI, body mass index; CG, cytosine phosphate guanine loci; DMP, differentially methylated positions; DNA methylation; FDR, false discovery rate; FGR, fetal growth restriction; GO, gene ontology; HOMA, homeostasis model assessment; ICR1, imprinting control region 1; MODY, maturity onset diabetes of the young; Marmal-aid; T2DM, type 2 diabetes mellitus; UCL, University College London; UCLH, University College London Hospital; UCSC, University of California Santa Cruz; fetal growth restriction; fetal origins of adult disease; placenta; transcription factor; umbilical cord.