DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood
DNA methylation mediates the association of prenatal famine exposure with higher adult BMI and serum triglyceride levels. Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metaboli...
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Published in | Science advances Vol. 4; no. 1; p. eaao4364 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for the Advancement of Science
01.01.2018
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Subjects | |
Online Access | Get full text |
ISSN | 2375-2548 2375-2548 |
DOI | 10.1126/sciadv.aao4364 |
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Summary: | DNA methylation mediates the association of prenatal famine exposure with higher adult BMI and serum triglyceride levels.
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 formal mediation 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 β 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-term metabolic health. The specific mechanism awaits elucidation. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. The consortium member names are listed in the acknowledgments. |
ISSN: | 2375-2548 2375-2548 |
DOI: | 10.1126/sciadv.aao4364 |