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BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Type 1 Diabetes | Research article

Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)

Authors: Sine Knorr, Anne Skakkebæk, Jesper Just, Emma B. Johannsen, Christian Trolle, Søren Vang, Zuzana Lohse, Birgitte Bytoft, Peter Damm, Kurt Højlund, Dorte M. Jensen, Claus H. Gravholt

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease.

Methods

Follow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012 and 2013.

Setting

Exploratory sub-study using data from the nationwide EPICOM study.

Participants

Adolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex, and postal code.

Main outcome measures

This study investigates DNA methylation using the 450K-Illumina Infinium assay and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples.

Results

We identified 9 hypomethylated and 5 hypermethylated positions (p < 0.005, |ΔM-value| > 1) and 38 up- and 1 downregulated genes (p < 0.005, log2FC ≥ 0.3) in adolescent offspring born to women with T1DM compared to controls. None of these findings remained significant after correction for multiple testing. However, we identified differences in gene co-expression networks, which could be of biological significance, using weighted gene correlation network analysis. Interestingly, one of these modules was significantly associated with offspring born to women with T1DM.
Functional enrichment analysis, using the identified changes in methylation and gene expression as input, revealed enrichment in disease ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling, and genes related to T1DM, obesity, atherosclerosis, and vascular pathologies. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX).

Conclusions

These findings suggest the possibility for intrauterine exposure to maternal T1DM to impact later in life methylation and gene expression in the offspring, a profile that may be linked to the increased risk of vascular and metabolic disease later in life.
Appendix
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Metadata
Title
Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)
Authors
Sine Knorr
Anne Skakkebæk
Jesper Just
Emma B. Johannsen
Christian Trolle
Søren Vang
Zuzana Lohse
Birgitte Bytoft
Peter Damm
Kurt Højlund
Dorte M. Jensen
Claus H. Gravholt
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02514-x

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