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Corresponding author. Email: bas.heijmans@lumc.nl

See publication for full list of BIOS Consortium.

E.W.T., L.H.L., and B.T.H. Methodology_ E.W.T., K.M.X., and E.W.v.Z. Investigation_ E.W.T., R.C.S., A.D.S., and L.H.L. Formal analysis_ E.W.T., R.L., and K.F.D. Validation_ K.F.D. Software_ E.W.T., R.L., and E.W.v.Z. Resources_ A.D.S., Biobank-based Integrative Omics Studies (BIOS) Consortium, and L.H.L. Data curation_ E.W.T., R.C.S., R.L., BIOS Consortium, A.D.S., and L.H.L. Writing (original draft)_ E.W.T., L.H.L., and B.T.H. Writing (review and editing)_ R.C.S., R.L., K.F.D., A.D.S., and P.E.S. Visualization_ E.W.T., R.L., and K.F.D. Supervision_ P.E.S., L.H.L., and B.T.H. Project administration_ L.H.L. and B.T.H. Funding acquisition_ E.W.T., P.E.S., L.H.L., and B.T.H_

We express our gratitude to the participants of the Dutch Hunger Winter Families study, the staff of TNO Quality of Life, the staff of the Department of Gerontology and Geriatrics Study Center at the Leiden University Medical Center (LUMC), and the LUMC Central Clinical Chemical Laboratory.

The authors declare that they have no competing interests.

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

Additional data related to this paper may be requested from the authors.


DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood


Journal Title:

Science Advances


Volume 4, Number 1


, Pages eaao4364-eaao4364

Type of Work:

Article | Final Publisher PDF


Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342, 596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formalmediation analysis.DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing b cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-termmetabolic health. The specific mechanism awaits elucidation.

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Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

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