Epigenetic Changes in Childhood Predict Risk of Obesity

April 10, 2014

By Will Boggs MD

NEW YORK (Reuters Health) - DNA methylation in the PCG1-alpha promoter is associated with an increased risk of obesity up to age 14 years independent of other factors, researchers from UK report.

Epigenetic regulation of various genes in early life has been postulated as a key mechanism in the development of obesity and other cardio-metabolic disease later in life, they write in Diabetes, in a paper released online March 12.

Dr. Karen A. Lillycrop from the University of Southampton and colleagues investigated whether differential methylation of CpG loci in the promoter region of peroxisomal proliferator-gamma-co-activator-1-alpha (PCG1-alpha) was related to adiposity, and whether differential methylation of any loci was associated with transcription factor binding.

Study subjects included 40 randomly selected children (20 boys, 20 girls) from the EarlyBird study whose blood was sampled at ages five to seven or eight to nine years and 14 years.

Methylation of individual CpG loci in the PCG1-alpha promoter appeared stable over time. Methylation at five to seven years predicted between 77% and 88% of the variation at 14 years, according to the researchers.

Methylation at four of seven specific CpG loci in the PCG1-alpha promoter at five to seven years significantly predicted future adiposity, whereas methylation at the three other loci showed no significant associations with future adiposity.

These associations were independent of sex, age at peak height velocity, physical activity and age.

Methylation of one of the predictive CpG loci modified binding of the pro-adipogenic PBX-1/HOXB9 complex, resulting in a marked decrease in PGC1-alpha promoter activity, the team found.

"In order to contribute causally to disease risk and have utility as biomarkers of disease risk differentially methylated loci induced early in life must be stable in the face of subsequent environmental change and have clinical relevance," the researchers note. "Our findings provide the first direct evidence that specific epigenetic marks measured in childhood can satisfy these criteria in relation to obesity."

Dr. Melanie Carless from Texas Biomedical Research Institute in San Antonio, Texas, has studied the relevance of epigenetic changes for obesity in Mexican Americans.

"The study that was conducted was very small (only 40 individuals) and only a single gene was looked at," said Dr. Carless, who was not involved in the new work. "Although the associations found in this paper were significant (for the small number of sites studied) and followed up with some potential functional validation, the p-values are not highly significant due to the small sample size and limited power to detect significant findings."

"To be convinced that this is a true finding, I think it is necessary to conduct a similar study in a much larger cohort," Dr. Carless told Reuters Health by email. "Further, looking at genome-wide changes in DNA methylation (by microarray or sequencing methods) would give a much bigger picture of the role that DNA methylation plays in childhood obesity."

"Therapies targeted at altering DNA methylation levels have been used for the treatment of cancer and since these produce a global effect, they are not likely to be useful for the treatment of all other complex diseases," she noted. "I therefore don't think that the findings of this paper would necessarily be translatable to clinical treatment. However, in general, the identification of genes that have altered DNA methylation levels, which contributes to disease, provides a gene target that may ultimately be manipulated for therapeutic intervention."

Because DNA methylation is thought to be a reversible process influenced by environmental factors, Dr. Carless explained, finding changes in DNA methylation levels tied to disease outcome may point to a prevention strategy.

"In the case of cardio-metabolic disease," she said, "if DNA methylation profiles indicate that you are at risk for the disease, you may be more inclined to improve your diet and increase exercise to counteract this."

Dr. Lillycrop did not respond to a request for comments.

SOURCE: http://bit.ly/1e4l3pX

Diabetes 2014.

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