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

Elmar W. Tobi, Roderick C. Slieker, René Luijk, Koen F. Dekkers, Aryeh D. Stein, Kate M. Xu, Biobank-based Integrative Omics Studies Consortium, P. Eline Slagboom, Erik W. van Zwet, L. H. Lumey, Bastiaan T. Heijmans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number4364
Number of pages10
JournalScience advances
Volume4
Issue number1
DOIs
Publication statusPublished - 31 Jan 2018

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Metabolic Diseases
DNA Methylation
Starvation
Triglycerides
Body Mass Index
Epigenomics
Health
Confidence Intervals
Glucose
Adipogenesis
Glycolysis
Lipid Metabolism
Energy Metabolism
Fats
Phosphates
Genome
Gene Expression
Pregnancy
Serum
Genes

Keywords

  • BLOOD
  • BODY-MASS INDEX
  • DATA RESOURCE
  • DUTCH FAMINE
  • EPIGENETIC EPIDEMIOLOGY
  • EPIGENOME-WIDE ASSOCIATION
  • EXPOSURE
  • HUNGER WINTER FAMILIES
  • IN-UTERO
  • MATERNAL SMOKING

Cite this

Tobi, Elmar W. ; Slieker, Roderick C. ; Luijk, René ; Dekkers, Koen F. ; Stein, Aryeh D. ; Xu, Kate M. ; Biobank-based Integrative Omics Studies Consortium ; Slagboom, P. Eline ; van Zwet, Erik W. ; Lumey, L. H. ; Heijmans, Bastiaan T. . / DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood. In: Science advances. 2018 ; Vol. 4, No. 1.
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title = "DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood",
abstract = "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.",
keywords = "BLOOD, BODY-MASS INDEX, DATA RESOURCE, DUTCH FAMINE, EPIGENETIC EPIDEMIOLOGY, EPIGENOME-WIDE ASSOCIATION, EXPOSURE, HUNGER WINTER FAMILIES, IN-UTERO, MATERNAL SMOKING",
author = "Tobi, {Elmar W.} and Slieker, {Roderick C.} and Ren{\'e} Luijk and Dekkers, {Koen F.} and Stein, {Aryeh D.} and Xu, {Kate M.} and {Biobank-based Integrative Omics Studies Consortium} and Slagboom, {P. Eline} and {van Zwet}, {Erik W.} and Lumey, {L. H.} and Heijmans, {Bastiaan T.}",
year = "2018",
month = "1",
day = "31",
doi = "10.1126/sciadv.aao4364",
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Tobi, EW, Slieker, RC, Luijk, R, Dekkers, KF, Stein, AD, Xu, KM, Biobank-based Integrative Omics Studies Consortium, Slagboom, PE, van Zwet, EW, Lumey, LH & Heijmans, BT 2018, 'DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood', Science advances, vol. 4, no. 1, 4364. https://doi.org/10.1126/sciadv.aao4364

DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood. / Tobi, Elmar W. ; Slieker, Roderick C. ; Luijk, René ; Dekkers, Koen F. ; Stein, Aryeh D. ; Xu, Kate M.; Biobank-based Integrative Omics Studies Consortium; Slagboom, P. Eline ; van Zwet, Erik W. ; Lumey, L. H. ; Heijmans, Bastiaan T. .

In: Science advances, Vol. 4, No. 1, 4364, 31.01.2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood

AU - Tobi, Elmar W.

AU - Slieker, Roderick C.

AU - Luijk, René

AU - Dekkers, Koen F.

AU - Stein, Aryeh D.

AU - Xu, Kate M.

AU - Biobank-based Integrative Omics Studies Consortium

AU - Slagboom, P. Eline

AU - van Zwet, Erik W.

AU - Lumey, L. H.

AU - Heijmans, Bastiaan T.

PY - 2018/1/31

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N2 - 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.

AB - 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.

KW - BLOOD

KW - BODY-MASS INDEX

KW - DATA RESOURCE

KW - DUTCH FAMINE

KW - EPIGENETIC EPIDEMIOLOGY

KW - EPIGENOME-WIDE ASSOCIATION

KW - EXPOSURE

KW - HUNGER WINTER FAMILIES

KW - IN-UTERO

KW - MATERNAL SMOKING

U2 - 10.1126/sciadv.aao4364

DO - 10.1126/sciadv.aao4364

M3 - Article

VL - 4

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 1

M1 - 4364

ER -