Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

Abstract

OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] = 0.013 [2.1 × 10−3], P value corrected for false discovery rate [PFDR] = 5.1 × 10−3) and cg02988288 (β [SE]−0.013 [2.3 × 10−3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSIONS Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.

Epigenetic changes associated with hyperglycaemia exposure in the longitudinal D.E.S.I.R. cohort

“…Moreover, an almost two-decade longitudinal study found that changes in TXNIP CpGs in type 1 diabetes were associated with an increased risk of later development of diabetic complications [26], [27]. In addition, in a recent study, we found a hypermethylation of two further probes in the TXNIP gene that were associated with fetal exposure of area under the curve of glucose during pregnancy [28], which was associated with T2D later in life and correlated with TXNIP gene expression in liver. Indeed, these studies demonstrate that this CpGs is differentially methylated prior to the diagnosis of established T2D (fasting glucose > 7 mmol/L), highlighting its potential importance as a predictor of T2D future development in early prediabetes states.…”

“…Additionally, we found that one of our most significant loci associated with T2D groups was located in the PTPRN2 gene. A recent study identified a hypermethylation in this gene was differentially methylated in pancreatic islets of a pre-diabetes mouse model [28]. The authors further confirmed a PTPRN2 hypermethylation was one of the strongest blood-based T2D predictive marker in the human (EPIC)-Potsdam cohort (median 3.8 years prior to T2D diagnosis) and also hypermethylated in pancreatic islets from T2D individuals [28].…”

“…A recent study identified a hypermethylation in this gene was differentially methylated in pancreatic islets of a pre-diabetes mouse model [28]. The authors further confirmed a PTPRN2 hypermethylation was one of the strongest blood-based T2D predictive marker in the human (EPIC)-Potsdam cohort (median 3.8 years prior to T2D diagnosis) and also hypermethylated in pancreatic islets from T2D individuals [28]. Indeed, our study found that a hypermethylation, also located in the gene body of PTPRN2 gene, was the second most significant differentially methylated site in our 3-6 years vs. control EWAS (Figure 2a).…”

Associations of Heavy Metals with Activities of Daily Living Disability: An Epigenome-Wide View of DNA Methylation and Mediation Analysis

“… 33 An epigenome-wide DNA methylation association study (EWAS) was prone to suffer inflation and bias of test statistics, 34 and a Bayesian method using R package BACON was proposed and widely used to control the amount of bias and inflation. 35 Inflated test statistics (lambda) was corrected using BACON, and p -values were estimated after correction for inflation and bias in the study. Previous studies of epigenome-wide analyses of DNA methylation using BACON package reported lambda varying from 0.79 to 1.40, 36 , 37 which supported the confidence of our study (lambda:1.29).…”

The link between gestational diabetes and cardiovascular diseases: potential role of extracellular vesicles

“…One mechanism by which this may occur is fetal metabolic reprogramming, involving epigenetic changes [ 102 ]. Differential DNA methylation profiles have been identified in umbilical cord blood and /or placenta obtained from infants of GDM pregnancies compared to normoglycemic pregnancies [ 15 , 34 , 36 , 103 – 105 ]. Differentially methylated genes include genes associated with CVD, metabolic diseases specifically type 2 diabetes, and immunological and endocrine disorders [ 51 , 103 ].…”