Gestational Diabetes and Maternal Obesity Are Associated with Epigenome-Wide Methylation Changes in Children
Open accessAbstract
Offspring of women with gestational diabetes mellitus (GDM) are at increased risk of developing metabolic disease, potentially mediated by epigenetic mechanisms. We recruited 608 GDM and 626 control offspring from the Danish National Birth Cohort, aged between 9 and 16 years. DNA methylation profiles were measured in peripheral blood of 93 GDM offspring and 95 controls using the Illumina HumanMethylation450 BeadChip. Pyrosequencing was performed for validation/replication of putative GDM-associated, differentially methylated CpGs in additional 905 offspring (462 GDM, 444 control offspring). We identified 76 differentially methylated CpGs in GDM offspring compared with controls in the discovery cohort (FDR, P < 0.05). Adjusting for offspring BMI did not affect the association between methylation levels and GDM status for any of the 76 CpGs. Most of these epigenetic changes were due to confounding by maternal prepregnancy BMI; however, 13 methylation changes were independently associated with maternal GDM. Three prepregnancy BMI–associated CpGs (cg00992687 and cg09452568 of ESM1 and cg14328641 of MS4A3 ) were validated in the replication cohort, while cg09109411 ( PDE6A ) was found to be associated with GDM status. The identified methylation changes may reflect developmental programming of organ disease mechanisms and/or may serve as disease biomarkers.
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After adjustment for maternal pre-pregnancy BMI, 13 CpG sites were identified as closely related to GDM.
“After adjustment for maternal pre-pregnancy BMI, 13 of these sites were identified as closely related to GDM”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [160]
Of the 13 GDM-related CpG sites, 9 were previously related to metabolic and cardiovascular diseases such as type II diabetes, obesity, diabetic nephropathy, or coronary heart disease.
“of which 9 were previously related to metabolic and cardiovascular diseases such as type II diabetes (T2D), obesity, diabetic nephropathy or coronary heart disease;”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [160]
20 CpG sites were associated with pre-pregnancy maternal obesity independently of GDM.
“moreover, 20 CpG sites were associated with pre-pregnancy maternal obesity independently of GDM [160].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [160]
In Hjort et al. 2018, venous blood analysis showed that 76 CpG sites were differently methylated in children exposed to GDM compared with control subjects (95 offspring of mothers with non-complicated pregnancies).
“Venous blood analysis showed that 76 CpG sites were differently methylated compared to control subjects (95 offspring of mothers with non-complicated pregnancies).”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [160]
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Self-citationEpigenetic Programming and Fetal Metabolic Programming
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Persistent Aortic Stiffness and Left Ventricular Hypertrophy in Children of Diabetic Mothers
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Hjort, L., Bredgaard, S. S., Manitta, E., Marques, I., Sørensen, A. E., Martino, D., Grunnet, L. G., Kelstrup, L., Houshmand-Oeregaard, A., Clausen, T. D., et al. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01673-3 · Cited by 6 · see citing works
Self-citation
- Authors
- Hjort, L., Martino, D., Grunnet, L. G., Naeem, H., Maksimovic, J., Olsson, A. H., Zhang, C., Ling, C., Olsen, S. F., Saffery, R., & Vaag, A. A.
- Affiliations
- University of Copenhagen (DK)
- The University of Melbourne (AU)
- Rigshospitalet (DK)
- National Institutes of Health (US)
- Lund University (SE)
- Statens Serum Institut (DK)
- Corresponding author
- Hjort, Line
- ORCID
- Venue
- JCI Insight
- Published
- 2018-09-06
- Volume
- 3
- Issue
- 17
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC6171795
- OpenAlex
- W2889958681
- Cited by
- 114
- References
- 7
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 11 · 2023: 18 · 2022: 15 · 2021: 26 · 2020: 22 · 2019: 9
- FWCI
- 15.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Strategiske Forskningsråd
- Innovationsfonden
- Gentofte Hospital
- Novo Nordisk
- Rigshospitalet
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Keywords
- gestational diabetes mellitus, maternal obesity, maternal pre-pregnancy BMI, DNA methylation, epigenetic programming, offspring, childhood, differentially methylated CpGs, ESM1, PDE6A, developmental programming, disease biomarkers, metabolic disease risk
- MeSH terms
- Adolescent, Adult, Child, Female, Humans, Male, Obesity, Pregnancy, Biomarkers, Diabetes, Gestational, Gene Expression Regulation, Developmental, DNA Methylation, Gene Expression Profiling, Epigenesis, Genetic
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