Associations between an Integrated Component of Maternal Glycemic Regulation in Pregnancy and Cord Blood DNA Methylation

Abstract

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.

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.

Keywords::

• cord blood
• DNA methylation
• insulinemia
• maternal glycemia
• oral glucose tolerance test
• pregnancy
• principal component analysis

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2021-0220

DL Juvinao-Quintero is the lead author of the study and conducted all analyses with the guidance of SM Lutz and MF Hivert, who participated in the study concept and design. DL Juvinao-Quintero wrote the manuscript with the help of SM Lutz and MF Hivert, who provided input on the interpretation of results and discussion. A Cardenas, P Perron and L Bouchard contributed to the interpretation of results and discussion and provided important feedback on the intellectual content of the paper. All authors read the manuscript and agreed with the final version. DL Juvinao-Quintero has full access to the data and is responsible for the integrity of the data and accuracy of the analyses.

Acknowledgments

The authors thank the participants of the Gen3G cohort who contributed to this study as well as clinical research nurses and research assistants for recruiting women and obtaining their informed consent. The authors also thank the Centre Hospitalier Universitaire de Sherbrooke biomedical laboratory for performing some of the assays used in this study. The authors acknowledge the editorial assistance of N Ghildayal and her contribution to the final version of the manuscript. Finally, the authors thank the Harvard Medical School for providing the computational resources required to conduct the analyses.

Financial & competing interests disclosure

This work presented in this study was supported by an American Diabetes Association Pathways Award (#1-15-ACE-26; M-F Hivert). Gen3G has also been supported by Fonds de Recherche du Québec en Santé (#20697; M-F Hivert), the Canadian Institute of Health Research (#MOP 115071; M-F Hivert) and Diabète Québec grants (P Perron and L Bouchard). DL Juvinao-Quintero was also supported by a Thomas O Pyle Fellowship from the Department of Population Medicine at the Harvard Pilgrim Health Care Institute. The work of SM Lutz was supported by a grant from the National Heart, Lung, and Blood Institute (K01HL125858). A Cardenas was supported by a grant from the National Institute of Environmental Health Sciences (R01ES031259). L Bouchard is a senior scholar at Fond de la Recherche du Québec en Santé. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

Institutional approval was obtained for Gen3G participants following the principles outlined in the Declaration of Helsinki. The institutional review board of the Centre Hospitalier Universitaire de Sherbrooke approved the study protocol (project: #07-027A1). In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data & materials availability

Access to data will be provided by us upon reasonable request.

Additional information

Funding

This work presented in this study was supported by an American Diabetes Association Pathways Award (#1-15-ACE-26; M-F Hivert). Gen3G has also been supported by Fonds de Recherche du Québec en Santé (#20697; M-F Hivert), the Canadian Institute of Health Research (#MOP 115071; M-F Hivert) and Diabète Québec grants (P Perron and L Bouchard). DL Juvinao-Quintero was also supported by a Thomas O Pyle Fellowship from the Department of Population Medicine at the Harvard Pilgrim Health Care Institute. The work of SM Lutz was supported by a grant from the National Heart, Lung, and Blood Institute (K01HL125858). A Cardenas was supported by a grant from the National Institute of Environmental Health Sciences (R01ES031259). L Bouchard is a senior scholar at Fond de la Recherche du Québec en Santé. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.