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2013 | 1 | 1-9

Article title

Exposure to Maternal Diabetes in Utero and DNA Methylation
Patterns in the Offspring


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Perturbations in early life environments, including intrauterine exposure
to maternal gestational diabetes (GDM), are hypothesized to lead to
metabolic imprinting resulting in increased risk of cardiometabolic
outcomes later in life. We aimed to 1) identify candidate genes and
biological pathways associated with differentially methylated regions
(DMRs) in relation to exposure to GDM in utero and, 2) using mediation
analysis, more definitively investigate the potential for mediation of the
effect of exposure to maternal diabetes in utero on cardiometabolic traits
in childhood risk through our identified DMRs. Genome-wide methylation
analysis of peripheral blood mononuclear cell’s DNA was conducted in 21
healthy children, ages 8-12 years. P-values from multiple linear regression
analyses for >27,000 CpG sites were ranked to identify DMRs between the
exposure groups. Among the top 10 ranked DMRs, we identified several
genes, including NPR1, PANK1, SCAND1, and GJA4, which are known
to be associated with cardiometabolic traits. Gene enrichment analysis of
the top 84 genes, each with p<=0.005, identified the ubiquitin proteasome
system (UPS) as the most enriched biological pathway (p = 0.07). The
UPS pathway reflects biological processes known to be associated with
endothelial function, inflammation, lipid metabolism, insulin resistance and
b-cell apoptosis, whose derangements are central to the pathogenesis
of cardiometabolic diseases. Increased methylation of PYGO1 and CLN8 had the greatest relative mediation effect (RME = 87%, p=0.005 and
RME=50%, p=0.01) on the impact of exposure to maternal diabetes in utero on VCAM-1 levels in the offspring. Multiple candidate genes and
the UPS were identified for future study as possible links between exposure
to maternal gestational diabetes in utero and adverse cardiometabolic traits
in the offspring. In particular, increased methylation of PYGO1 and CLN8 may be biological links between intrauterine exposure to maternal diabetes
and significantly increased VCAM-1 levels in the offspring.







Physical description


04 - 02 - 2013
08 - 03 - 2013
12 - 12 - 2012


  • Department of Epidemiology,
    University of Colorado Anschutz Medical
    Campus, Aurora, Colorado, USA
  • Department of Biostatistics
    and Informatics, University of Colorado
    Anschutz Medical Campus,
    Aurora, Colorado, USA
  • Department of Epidemiology,
    University of Colorado Anschutz Medical
    Campus, Aurora, Colorado, USA


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