https://orcid.org/0000-0002-9341-918X
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Abstract
Background: Gestational hyperglycemia is associated with adverse perinatal outcomes and long-term offspring metabolic programming, likely through dysregulation of DNA methylation (DNAm). Materials & methods: We tested associations between maternal HbA1c and cord blood DNAm among 412 mother–child pairs in the genetics of glucose regulation in gestation and growth (Gen3G) and implemented Mendelian randomization to infer causality. We sought replication in an independent sample from Healthy Start. Results: Higher second trimester HbA1c levels were associated with lower DNAm at cg21645848 (p = 3.9 × 10-11) near URGCP. Mendelian randomization and replication analyses showed same direction of effect between HbA1c and DNAm at cg21645848, but did not reach statistical significance. Conclusion: We found that higher maternal glycemia reflected by HbA1c is associated with cord blood DNAm at URGCP, a gene related with inflammatory pathways.
Lay abstract:An adverse metabolic environment in utero, such as elevated maternal blood glucose levels, may have long-lasting impacts on child development. Studies show that maternal glucose can cross the placenta and may impact regulatory markers acting upon genes through epigenetics. We investigated associations between 3 month maternal glucose levels, reflected by HbA1c, during pregnancy and cord blood DNA methylation (one type of epigenetic marker) in two prospective cohorts of mother–child pairs. We found that higher maternal blood glucose levels were associated with lower cord blood DNA methylation near a gene called URGCP, suggesting potential influence of elevated maternal glucose on inflammatory pathways in the newborn.
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-2020-0279
DL Juvinao-Quintero and MF Hivert participated in the study concept and design. DL Juvinao-Quintero conducted analyses for Gen3G and wrote the manuscript. D Dabelea provided access to data in the Healthy Start cohort and AP Starling conducted the replication analyses for this cohort. A Cardenas, CE Powe, P Perron and L Bouchard contributed with interpretation of analyses and discussion. All authors read the manuscript, contributed to the discussion with important intellectual content, and agreed with its final version. DL Juvinao-Quintero has access to data presented in this study and is responsible for the integrity of the data and accuracy of the data analysis.
Acknowledgments
We thank participants of the Gen3G and the Healthy Start cohorts who contributed to this study, as well as clinical research nurses and research assistants in each study for recruiting women and obtaining consent. We also thank the CHUS biomedical laboratory for performing some assays in the Gen3G study. Last, we thank the Harvard Medical School for providing the computational resources required to conduct the analyses.
Financial & competing interests disclosure
Gen3G work presented in this study was supported by an American Diabetes Association Pathways Award #1-15-ACE-26 (MFH); Gen3G has also been supported by Fonds de recherche du Québec en santé #20697 (MFH); Canadian Institute of Health Research #MOP 115071 (MFH), and Diabète Québec grants (P Perron and L Bouchard). DLJQ is also supported by a Pyle fellowship in the Department of Population Medicine at Harvard Pilgrim Health Care Institute. The Healthy Start study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076648), the National Institutes of Health Office of the Director (UH3OD023248), and the National Institute of Environmental Health Sciences (R01ES022934). AP Starling was supported by a grant from the National Institute of Environmental Health Sciences (R00ES025817) as well as AC (R01ES031259). CE Powe is supported by NIH K23DK113218 and the Robert Wood Johnson Foundation’s Harold Amos Medical Faculty Development Program. 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
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
Data sharing statement
Access to data will be available by the authors upon reasonable request.