PMID- 29399631
OWN - NLM
STAT- MEDLINE
DCOM- 20190904
LR  - 20231105
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 4
IP  - 1
DP  - 2018 Jan
TI  - DNA methylation as a mediator of the association between prenatal adversity and 
      risk factors for metabolic disease in adulthood.
PG  - eaao4364
LID - 10.1126/sciadv.aao4364 [doi]
LID - eaao4364
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 beta 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.
FAU - Tobi, Elmar W
AU  - Tobi EW
AUID- ORCID: 0000-0002-1378-3687
AD  - Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
AD  - Division of Human Nutrition, Wageningen University and Research, 6708 WE 
      Wageningen, Netherlands.
FAU - Slieker, Roderick C
AU  - Slieker RC
AD  - Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
FAU - Luijk, Rene
AU  - Luijk R
AD  - Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
AD  - Medical Statistics, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
FAU - Dekkers, Koen F
AU  - Dekkers KF
AD  - Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
FAU - Stein, Aryeh D
AU  - Stein AD
AUID- ORCID: 0000-0003-1138-6458
AD  - Hubert Department of Global Health, Rollins School of Public Health, Emory 
      University, Atlanta, GA 30322, USA.
FAU - Xu, Kate M
AU  - Xu KM
AUID- ORCID: 0000-0002-1863-9676
AD  - Medical Statistics, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
AD  - Faculty of Psychology and Educational Sciences, Welten Institute, Open University 
      of the Netherlands, 6419 AT Heerlen, Netherlands.
CN  - Biobank-based Integrative Omics Studies Consortium
FAU - Slagboom, P Eline
AU  - Slagboom PE
AUID- ORCID: 0000-0002-2875-4723
AD  - Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
FAU - van Zwet, Erik W
AU  - van Zwet EW
AUID- ORCID: 0000-0001-5537-3179
AD  - Medical Statistics, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
FAU - Lumey, L H
AU  - Lumey LH
AD  - Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
AD  - Department of Epidemiology, Mailman School of Public Health, Columbia University, 
      New York, NY 10032, USA.
FAU - Heijmans, Bastiaan T
AU  - Heijmans BT
AUID- ORCID: 0000-0001-5918-0534
AD  - Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University 
      Medical Center, 2300 RC Leiden, Netherlands.
LA  - eng
GR  - R01 AG042190/AG/NIA NIH HHS/United States
GR  - R01 HL067914/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180131
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
RN  - 0 (Triglycerides)
SB  - IM
MH  - Adult
MH  - Body Mass Index
MH  - DNA Methylation/*genetics
MH  - Female
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Metabolic Diseases/blood/*genetics
MH  - Middle Aged
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects/*genetics
MH  - Risk Factors
MH  - Starvation
MH  - Triglycerides/blood
PMC - PMC5792223
EDAT- 2018/02/06 06:00
MHDA- 2019/09/05 06:00
PMCR- 2018/01/31
CRDT- 2018/02/06 06:00
PHST- 2017/07/21 00:00 [received]
PHST- 2018/01/03 00:00 [accepted]
PHST- 2018/02/06 06:00 [entrez]
PHST- 2018/02/06 06:00 [pubmed]
PHST- 2019/09/05 06:00 [medline]
PHST- 2018/01/31 00:00 [pmc-release]
AID - aao4364 [pii]
AID - 10.1126/sciadv.aao4364 [doi]
PST - epublish
SO  - Sci Adv. 2018 Jan 31;4(1):eaao4364. doi: 10.1126/sciadv.aao4364. eCollection 2018 
      Jan.