Background: Previous studies suggest that fetal programming to hyperglycemia in pregnancy is due to modulation of DNA methylation (DNAm), but they have been limited in their maternal glycemic characterization. Methods: In the Gen3G study, we used a principal component analysis to integrate multiple glucose and insulin values measured during the second trimester oral glucose tolerance test. We investigated associations between principal components and cord blood DNAm levels in an epigenome-wide analysis among 430 mother-child pairs. Results: The first principal component was robustly associated with lower DNAm at cg26974062 (TXNIP; p = 9.9 × 10-9) in cord blood. TXNIP is a well-known DNAm marker for type 2 diabetes in adults. Conclusion: We hypothesize that abnormal glucose metabolism in pregnancy may program dysregulation of TXNIP across the life course.
Keywords: DNA methylation; cord blood; insulinemia; maternal glycemia; oral glucose tolerance test; pregnancy; principal component analysis.
Lay abstract Elevated maternal levels of glucose affect the in utero environment and play a crucial role in the adequate development of the fetus and the long-term health of the child. Increasing evidence shows that a regulatory process called DNA methylation (DNAm), which affects gene expression, may be an epigenetic mechanism responsible for linking in utero exposures and long-term health. In this study, we derived a marker reflecting elevated maternal glucose and insulin levels during pregnancy. Next, we used this marker to assess its association with DNAm measured in the child's cord blood collected at delivery. We found that overall higher circulating levels of both maternal glucose and insulin in pregnancy were related to cord blood DNAm at a gene called TXNIP. This gene has been previously recognized as a type 2 diabetes epigenetic signature in blood cells of adults from different populations. Thus, we may have identified a cord blood DNAm marker that signals long-term risk of diabetes over the life course.