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Cited by 144Gestational Diabetes Research and ManagementEpigenetics and DNA MethylationBirth, Development, and Health

Increased global placental DNA methylation levels are associated with gestational diabetes

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Reichetzeder, C., Dwi Putra, S. E., Pfab, T., Slowinski, T., Neuber, C., Kleuser, B., Hocher, B.·2016·Clinical Epigenetics
DOI 10.1186/s13148-016-0247-9PMC PMC4960714
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Abstract

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes. It is known that GDM is associated with an altered placental function and changes in placental gene regulation. More recent studies demonstrated an involvement of epigenetic mechanisms. So far, the focus regarding placental epigenetic changes in GDM was set on gene-specific DNA methylation analyses. Studies that robustly investigated placental global DNA methylation are lacking. However, several studies showed that tissue-specific alterations in global DNA methylation are independently associated with type 2 diabetes. Thus, the aim of this study was to characterize global placental DNA methylation by robustly measuring placental DNA 5-methylcytosine (5mC) content and to examine whether differences in placental global DNA methylation are associated with GDM. METHODS: Global DNA methylation was quantified by the current gold standard method, LC-MS/MS. In total, 1030 placental samples were analyzed in this single-center birth cohort study. RESULTS: Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 ± 0.63 vs. 3.00 ± 0.46 %; p = 0.013; ±SD). Bivariate logistic regression showed a highly significant positive correlation between global placental DNA methylation and the presence of GDM (p = 0.0009). Quintile stratification according to placental DNA 5mC levels revealed that the frequency of GDM was evenly distributed in quintiles 1-4 (2.9-5.3 %), whereas the frequency in the fifth quintile was significantly higher (10.7 %; p = 0.003). Bivariate logistic models adjusted for maternal age, BMI, ethnicity, recurrent miscarriages, and familiar diabetes predisposition clearly demonstrated an independent association between global placental DNA hypermethylation and GDM. Furthermore, an ANCOVA model considering known predictors of DNA methylation substantiated an independent association between GDM and placental DNA methylation. CONCLUSIONS: This is the first study that employed a robust quantitative assessment of placental global DNA methylation in over a thousand placental samples. The study provides large scale evidence that placental global DNA hypermethylation is associated with GDM, independent of established risk factors.

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  • DNA methylation is important in the regulation of gene expression associated with metabolic disturbances in pregnant women and in the metabolic programming of the fetus in the setting of GDM-induced hyperglycemia.

    “A growing body of research provides evidence of the importance of DNA methylation in the regulation of gene expression associated with metabolic disturbances in pregnant women and in the metabolic programming of the fetus in the setting of GDM-induced hyperglycemia [56,57,58].”

    From Gestational Diabetes Mellitus—Recent Literature Review (2022) · cites this paper as [57]

    The Background (page unavailable) links GDM to altered placental gene regulation and epigenetic mechanisms, and separately says that fetal exposure to GDM might contribute to later metabolic programming. The Discussion reports an association between placental DNA methylation and GDM, but the paper does not establish that methylation regulates gene expression in pregnant women or drives fetal metabolic programming under GDM-induced hyperglycemia. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Hypermethylation is associated with developmental defects, such as gestational diabetes and Down's syndrome.

    “Moreover, hypermethylation is associated with developmental defects, such as gestational diabetes and Down’s syndrome [181, 182].”

    From Air pollution and children’s health—a review of adverse effects associated with prenatal exposure from fine to ultrafine particulate matter (2021) · cites this paper as [181]

    The Results and Conclusions report an association between increased global placental DNA methylation and gestational diabetes. The paper does not address Down’s syndrome or establish hypermethylation as associated with developmental defects as a category; it also leaves the direction of the relationship with gestational diabetes unresolved. The indexed passages have no page numbers. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • GDM is associated with placenta global DNA hypermethylation.

    “Some recent studies have reported that GDM is associated with placenta global DNA hypermethylation [154].”

    From The Pathophysiology of Gestational Diabetes Mellitus (2018) · cites this paper as [154]

  • Mothers with GDM displayed significantly increased global placental DNA methylation (3.22 ± 0.63 vs. 3.00 ± 0.46%, p = 0.013).

    “Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 ± 0.63 vs. 3.00 ± 0.46% (±SD), p = 0.013) [57].”

    From Gestational Diabetes Mellitus—Recent Literature Review (2022) · cites this paper as [57]

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Authors
Reichetzeder, C., Dwi Putra, S. E., Pfab, T., Slowinski, T., Neuber, C., Kleuser, B., & Hocher, B.
Affiliations
  • University of Potsdam (DE)
  • Charité – Universitätsmedizin Berlin (DE)
  • Hunan Normal University (CN)
Corresponding author
Hocher, B.
ORCID
Venue
Clinical Epigenetics
Publisher
Springer Science and Business Media LLC
Published
2016-07-26
Volume
8
Issue
1
Pages
82-82
ISSN
  • 1868-7075 (ISSN-L)
  • 1868-7083
DOI
10.1186/s13148-016-0247-9
PMC
PMC4960714
OpenAlex
W2502871139
Cited by
144
References
1
Citations by year
2026: 7 · 2025: 9 · 2024: 9 · 2023: 22 · 2022: 14 · 2021: 20 · 2020: 14 · 2019: 19 · 2018: 20 · 2017: 9 · 2016: 1
FWCI
21.10
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Clinical Epigenetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • publish.UP (University of Potsdam) (submittedVersion, cc-by)
  • publish.UP (University of Potsdam) (submittedVersion)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • Ubaya Repository (University of Surabaya) (submittedVersion)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
Funders
Deutsche Forschungsgemeinschaft (Ho1665/5-2)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
gestational diabetes mellitus, placental DNA methylation, 5-methylcytosine, placenta, epigenetics, placental function, type 2 diabetes risk
MeSH terms
Adult, Female, Humans, Placenta, Pregnancy, Pregnancy Outcome, Cohort Studies, Logistic Models, Diabetes, Gestational, DNA Methylation, Epigenesis, Genetic, 5-Methylcytosine, Genome-Wide Association Study

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