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

Abstract

<b>OBJECTIVE</b> <p>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. </p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>To address this hypothesis, we conducted fixed-effect 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 (N<sub>max</sub>= 3,503), insulin (N<sub>max</sub>= 2,062), and the area under the curve of glucose (AUC<sub>gluc</sub>) following oral glucose tolerance tests (OGTT, N<sub>max</sub>= 1,505). We performed look-up analyses for identified CpG dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression.</p> <p><b>RESULTS</b></p> <p>Greater maternal AUC<sub>gluc</sub> was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β= -0.013 [SE=2.1x10<sup>-3</sup>], P<sub>FDR</sub>= 5.1x10<sup>-3</sup>) and cg02988288 (β= -0.013 [SE=2.3x10<sup>-3</sup>], P<sub>FDR</sub> =0.031) in <i>TXNIP</i>. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near <i>TXNIP</i> was associated with multiple metabolic traits later in life, including type 2 diabetes. <i>TXNIP</i> DNAm in liver biopsies was associated with hepatic expression<i> </i>of <i>TXNIP</i>. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm.</p> <p><b>CONCLUSION</b></p> <p>Maternal hyperglycemia, as reflected by AUC<sub>gluc</sub>, was associated with lower cord blood DNAm at <i>TXNIP</i>. <a>Associations between DNAm at these CpGs and metabolic traits in subsequent look-up analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses</a>.</p>