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

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 g...

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Autores principales: Knorr, Sine, Skakkebæk, Anne, Just, Jesper, Johannsen, Emma B., Trolle, Christian, Vang, Søren, Lohse, Zuzana, Bytoft, Birgitte, Damm, Peter, Højlund, Kurt, Jensen, Dorte M., Gravholt, Claus H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9503228/
https://www.ncbi.nlm.nih.gov/pubmed/36138412
http://dx.doi.org/10.1186/s12916-022-02514-x
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author Knorr, Sine
Skakkebæk, Anne
Just, Jesper
Johannsen, Emma B.
Trolle, Christian
Vang, Søren
Lohse, Zuzana
Bytoft, Birgitte
Damm, Peter
Højlund, Kurt
Jensen, Dorte M.
Gravholt, Claus H.
author_facet Knorr, Sine
Skakkebæk, Anne
Just, Jesper
Johannsen, Emma B.
Trolle, Christian
Vang, Søren
Lohse, Zuzana
Bytoft, Birgitte
Damm, Peter
Højlund, Kurt
Jensen, Dorte M.
Gravholt, Claus H.
author_sort Knorr, Sine
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02514-x.
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spelling pubmed-95032282022-09-24 Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study) Knorr, Sine Skakkebæk, Anne Just, Jesper Johannsen, Emma B. Trolle, Christian Vang, Søren Lohse, Zuzana Bytoft, Birgitte Damm, Peter Højlund, Kurt Jensen, Dorte M. Gravholt, Claus H. BMC Med Research Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02514-x. BioMed Central 2022-09-23 /pmc/articles/PMC9503228/ /pubmed/36138412 http://dx.doi.org/10.1186/s12916-022-02514-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Knorr, Sine
Skakkebæk, Anne
Just, Jesper
Johannsen, Emma B.
Trolle, Christian
Vang, Søren
Lohse, Zuzana
Bytoft, Birgitte
Damm, Peter
Højlund, Kurt
Jensen, Dorte M.
Gravholt, Claus H.
Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)
title Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)
title_full Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)
title_fullStr Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)
title_full_unstemmed Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)
title_short Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)
title_sort epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the epicom study)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9503228/
https://www.ncbi.nlm.nih.gov/pubmed/36138412
http://dx.doi.org/10.1186/s12916-022-02514-x
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