Genome-Wide Placental Gene Methylations in Gestational Diabetes Mellitus, Fetal Growth and Metabolic Health Biomarkers in Cord Blood

Abstract

Gestational diabetes mellitus (GDM) “program” an elevated risk of metabolic syndrome in the offspring. Epigenetic alterations are a suspected mechanism. GDM has been associated with placental DNA methylation changes in some epigenome-wide association studies. It remains unclear which genes or pathways are affected, and whether any placental differential gene methylations are correlated to fetal growth or circulating metabolic health biomarkers. In an epigenome-wide association study using the Infinium MethylationEPIC Beadchip, we sought to identify genome-wide placental differentially methylated genes and enriched pathways in GDM, and to assess the correlations with fetal growth and metabolic health biomarkers in cord blood. The study samples were 30 pairs of term placentas in GDM vs. euglycemic pregnancies (controls) matched by infant sex and gestational age at delivery in the Shanghai Birth Cohort. Cord blood metabolic health biomarkers included insulin, C-peptide, proinsulin, IGF-I, IGF-II, leptin and adiponectin. Adjusting for maternal age, pre-pregnancy BMI, parity, mode of delivery and placental cell type heterogeneity, 256 differentially methylated positions (DMPs,130 hypermethylated and 126 hypomethylated) were detected between GDM and control groups accounting for multiple tests with false discovery rate <0.05 and beta-value difference >0.05. WSCD2 was identified as a differentially methylated gene in both site- and region-level analyses. We validated 7 hypermethylated (CYP1A2, GFRA1, HDAC4, LIMS2, NAV3, PAX6, UPK1B) and 10 hypomethylated (DPP10, CPLX1, CSMD2, GPR133, NRXN1, PCSK9, PENK, PRDM16, PTPRN2, TNXB) genes reported in previous epigenome-wide association studies. We did not find any enriched pathway accounting for multiple tests. DMPs in 11 genes (CYP2D7P1, PCDHB15, ERG, SIRPB1, DKK2, RAPGEF5, CACNA2D4, PCSK9, TSNARE1, CADM2, KCNAB2) were correlated with birth weight (z score) accounting for multiple tests. There were no significant correlations between placental gene methylations and cord blood biomarkers. In conclusions, GDM was associated with DNA methylation changes in a number of placental genes, but these placental gene methylations were uncorrelated to the observed metabolic health biomarkers (fetal growth factors, leptin and adiponectin) in cord blood. We validated 17 differentially methylated placental genes in GDM, and identified 11 differentially methylated genes relevant to fetal growth.

Promotion effect of FGF23 on osteopenia in congenital scoliosis through FGFr3/TNAP/OPN pathway

“…Considering that fetal vertebral malformation arises in the early stage of pregnancy, but X-ray irradiation and other examination methods cannot be used at this stage of pregnancy due to radiation risks and other reasons, it is of great clinical significance to develop an accurate and easy marker for the early diagnosis of CS. [30,31] However, due to the lack of maternal peripheral blood or umbilical cord blood samples taken during pregnancy, it is impossible to know at this point whether the levels of FGF23 mRNA in the maternal blood change during pregnancy when CS is present in the fetus. Therefore, whether the levels of FGF23 mRNA can be used for the early diagnosis of patients with CS needs further study.…”

Placental DNA methylation analysis of selective fetal growth restriction in monochorionic twins reveals aberrant methylated CYP11A1 gene for fetal growth restriction

“…The methylation state in the PTPRN2 gene has been known to be correlated to gestational diabetes mellitus, with a hypomethylated PTPRN2 gene in the placenta and cord blood. 28 The enrichment terms mainly included neuron projection, receptor complex, cell projection, and a component of plasma membrane. In our study, the PTPRN2 gene had the largest number of differential CpGs sites, which may influence transcriptional function towards assigning metabolic function.…”

Questions Regarding Variants in ADIPOQ in Maternal Circulating Adipokine Profile in Gestational Diabetes Mellitus [Letter]

“… 4 However, the expression of adiponectin receptors in gestational diabetes mellitus patients could not be detected, while a study on methylation has been reported previously. 5 An additional thoughtful response to this interesting study is that the detection of polymorphisms of the ADIPOQ gene in the study model of Macaca fascicularis was suggested to be performed in future research, such as that performed in a previous study. 6 …”