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Epigenetics. 2018 Nov 9:1-16. doi: 10.1080/15592294.2018.1543503. [Epub ahead of print]

DNA methylation in blood as a mediator of the association of mid-childhood body mass index with cardio-metabolic risk score in early adolescence.

Author information

1
a Department of Environmental Health Sciences , Columbia Mailman School of Public Health , NY , NY , USA.
2
b School of Public Health, Li Ka Shing Faculty of Medicine , The University of Hong Kong , Hong Kong SAR , People's Republic of China.
3
c Department of Population Medicine , Harvard Medical School and Harvard Pilgrim Health Care Institute , Boston , MA , USA.
4
d Department of Environmental Medicine & Public Health , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
5
e Graduate School of Public Health and Health Policy , City University of New York , New York , USA.
6
f Center for Population Epigenetics, Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
7
g Department of Preventive Medicine, Feinberg School of Medicine , Northwestern University , Chicago , IL , USA.
8
h Division of Pediatric Pulmonary Medicine, Department of Pediatrics , University of Rochester Medical Center , Rochester , NY , USA.
9
i Channing Division of Network Medicine , Brigham and Women's Hospital , Boston , MA , USA.
10
j Department of Medicine , Harvard Medical School , Boston , MA , USA.
11
k Division of Pulmonary and Critical Care Medicine , Brigham and Women's Hospital , Boston , MA , USA.
12
l Department of Biostatistics, Harvard T.H. Chan School of Public Health , Harvard University , Boston , MA , USA.
13
m Department of Nutrition, Harvard T.H. Chan School of Public Health , Harvard University , Boston , MA , USA.
14
n Diabetes Unit , Massachusetts General Hospital , Boston , MA , USA.

Abstract

Obesity is associated with higher cardio-metabolic risk even in childhood and adolescence; whether this association is mediated by epigenetic mechanisms remains unclear. We examined the extent to which mid-childhood body mass index (BMI) z-score (median age 7.7 years) was associated with cardio-metabolic risk score in early adolescence (median age 12.9 years) via mid-childhood DNA methylation among 265 children in the Project Viva. We measured DNA methylation in leukocytes using the Infinium Human Methylation450K BeadChip. We assessed mediation CpG-by-CpG using epigenome-wide association analyses, high-dimensional mediation analysis, and natural effect models. We observed mediation by mid-childhood DNA methylation at 6 CpGs for the association between mid-childhood BMI z-score and cardio-metabolic risk score in early adolescence in the high-dimensional mediation analysis (accounting for 10% of the total effect) and in the natural effect model (β = 0.04, P = 3.2e-2, accounting for 13% of the total effect). The natural direct effect of BMI z-score on cardio-metabolic risk score was still evident (β = 0.27, P = 1.1e-25). We also observed mediation by mid-childhood DNA methylation at 5 CpGs that was in the opposite direction from the total effect (natural effect model: β = -0.04, P = 2.0e-2). Mediation in different directions implies a complex role of DNA methylation in the association between BMI and cardio-metabolic risk and needs further investigation. Future studies with larger sample size and greater variability in cardio-metabolic risk will further help elucidate the role of DNA methylation for cardio-metabolic risk.

KEYWORDS:

BMI; DNA methylation; Obesity; cardio-metabolic; epigenetics; mediation

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