Abstract
PurposeAltered methylation at Insulin-like Growth Factor 2 (IGF2) regulatory regions has previously been associated with obesity, and several malignancies including colon, esophageal, and prostate adenocarcinomas, presumably via changes in expression and/or loss of imprinting, but the functional significance of these DNA methylation marks have not been demonstrated in humans. We examined associations among DNA methylation at IGF2 differentially methylated regions (DMRs), circulating IGF2 protein concentrations in umbilical cord blood (UCB) and birth weight in newborns.MethodsQuestionnaire data were obtained from 300 pregnant women recruited between 2005 and 2009. UCB DNA methylation was measured by bisulfite pyrosequencing. UCB plasma concentrations of soluble IGF2 were measured by ELISA assays. Generalized linear regression models were used to examine the relationship between DMR methylation and IGF2 levels.ResultsLower IGF2 DMR methylation was associated with elevated plasma IGF2 protein concentrations (β = −9.87, p < 0.01); an association that was stronger in infants born to obese women (pre-pregnancy BMI > 30 kg/m2, β = −20.21, p < 0.0001). Elevated IGF2 concentrations were associated with higher birth weight (p < 0.0001) after adjusting for maternal race/ethnicity, pre-pregnancy BMI, cigarette smoking, gestational diabetes, and infant sex. These patterns of association were not apparent at the H19 DMR.ConclusionOur data suggest that variation in IGF2 DMR methylation is an important mechanism by which circulating IGF2 concentrations, a putative risk factor for obesity and cancers of the colon, esophagus, and prostate, are modulated; associations that may depend on pre-pregnancy obesity.
Highlights
The ‘developmental origins of adult disease susceptibility’ hypothesis posits that environmental exposures early in the development permanently alter the phenotype, influencing susceptibility to lifetime risk of obesity and several cancers [1]
Purpose Altered methylation at Insulin-like Growth Factor 2 (IGF2) regulatory regions has previously been associated with obesity, and several malignancies including colon, esophageal, and prostate adenocarcinomas, presumably via changes in expression and/or loss of imprinting, but the functional significance of these DNA methylation marks have not been demonstrated in humans
Our data suggest that variation in IGF2 differentially methylated regions (DMRs) methylation is an important mechanism by which circulating IGF2 concentrations, a putative risk factor for obesity and cancers of the colon, esophagus, and prostate, are modulated; associations that may depend on pre-pregnancy obesity
Summary
The ‘developmental origins of adult disease susceptibility’ hypothesis posits that environmental exposures early in the development permanently alter the phenotype, influencing susceptibility to lifetime risk of obesity and several cancers [1]. The most stable and wellstudied epigenetic mechanism is DNA methylation, which involves the covalent attachment of a methyl group to the 5-carbon position of the pyrimidine ring of cytosine residues when in 50-CpG-30 context. This epigenetic modification is faithfully transmitted to nascent DNA molecules during DNA replication and is maintained during somatic cell proliferation. Cancer prevention will require identification of aberrant epigenetic profiles driving risk, demonstration of their functional significance as well as environmental exposures associated with their perturbation and ‘windows’ of susceptibility during life’s course
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