Study on the relationship between DNA methylation of target CpG sites in peripheral blood and gestational diabetes during early pregnancy

Abstract

Genome-wide DNA methylation profiling have been used to find maternal CpG sites related to the occurrence of gestational diabetes mellitus (GDM). However, none of these differential sites found has been verified in a larger sample. Here, our aim was to evaluate whether first trimester changes in target CpG sites in the peripheral blood of pregnancy women predict subsequent development of GDM. This nested case–control study was based upon an early pregnancy follow-up cohort (ChiCTR1900020652). Target CpG sites were extracted from related published literature and bioinformatics analysis. The DNA methylation levels at 337 CpG sites of 80 GDM cases and 80 matched healthy controls during the early pregnancy (10–15 weeks) were assessed using MethylTarget sequencing. The best cut-off level for methylation of CpG site was determined using the generated ROC curve. The independent effect of CpG site methylation status on GDM was analyzed using conditional logistic regression. Methylation levels at 6 CpG sites were significantly higher in the GDM group than in controls, whereas those at another 6 CpG sites were significantly lower (FDR < 0.05). The area under the ROC curve at each methylation level of the significant CpG sites ranged between 0.593 and 0.650 for the occurrence of GDM. After adjusting for possible confounders, the hypermethylation status of CpG site 68167324 (OR = 3.168, 1.038–9.666) and 24837915 (OR = 5.232, 1.659–16.506) was identified as more strongly associated with GDM; meanwhile, the hypermethylation of CpG site 157130156 (OR = 0.361, 0.135–0.966) and 89438648 (OR = 0.206, 0.065–0.655) might indicate lower risk of GDM. The methylation status of target CpG sites in the peripheral blood of pregnant women during the first trimester may be associated with GDM pathogenesis, and has potential as a predictor of GDM.

Genetics and Epigenetics: Implications for the Life Course of Gestational Diabetes

“…A limited number of studies have examined DNA methylation in blood cells collected from women early in pregnancy (less than 20 weeks gestation) [ 99 , 100 , 101 ]. Two studies performed an eWAS, but both were small (11 and 6 cases with the same number of women with normoglycemia during pregnancy).…”

“…One of the hypomethylated sites was in CDKN2B , which is within a genetic locus associated with T2DM and encodes cyclin-dependent kinase inhibitor 2B. Finally, Wang et al examined 337 CpG sites in peripheral blood collected at 10–15 weeks gestation from 80 women with GDM and 80 normoglycemic women [ 100 ]. The 337 sites were chosen based on findings from earlier studies.…”

Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis

“…Usually, gene activation is linked to hypomethylation of promoters of genes, whereas gene silencing is associated with hypermethylation [ 114 ]. Several studies have been performed to study the DNA methylation profile in GDM [ 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 ].…”

“…In a very recent study, Wang et al assessed DNA methylation levels at 337 GDM-related CpG sites using MethylTarget sequencing [ 129 ]. Peripheral blood samples were collected at an early pregnancy stage from 80 GDM cases and 80 healthy controls.…”

“…On the other hand, qualitative analysis identified eight CpG sites that differed between the groups, located in the intron region of C5orf34 and promoter regions of RDH 12 , HAPLN3 , YAP1 , DNAJB6 , and NFATC4 . The hypermethylation of the following two CpG sites was correlated with increased GDM risk: CpG site 68,167,324 located in RDH 12 , and CpG site 24,837,915 located in the promoter region of NFATC4 [ 129 ].…”