Beyond Genetics, DNA Methylation Identified as New Factor in Obesity

DNA methylation may join body mass index, adiposity, and gene expression as another factor that predisposes certain individuals to develop obesity, obesity-related conditions.

With Michael Mendelson, MD, ScM, and Priyathama Vellanki, MD

Genetics may contribute to excessive and undesirable weight gain in some people, but it doesn't fully explain the wide variation in overweight across the population, or why some people who have obesity manage to avoid comorbid conditions, such as diabetes and hyperlipidemia.

In searching for clues, new research identified DNA methylation as a possible link between body mass index (BMI) and obesity-related disease,1 led by study author Michael Mendelson, MD, ScM, a research fellow at the National Heart, Lung and Blood Institute and a pediatric cardiologist at Boston Children's Hospital.   

DNA methylation is a form of epigenetic modification that controls whether genes are turned on or off. The findings,1 reported in PLOS Medicine, "'may hold important information for who is at risk for obesity-related diseases," Dr. Mendelson told Endocrine Web.

Beyond genetics, DNA methylation has been identified as new factor in development of obesity.

The research looked beyond known genetic influences that have been linked to obesity, said Dr. Mendelson.     

"I think we are coming to the realization that changes in your genetic sequence aren’t explaining everything we see in obesity and obesity-related diseases," Dr. Mendelson said. "We are finding lots of changes in how genes are regulated."

Appreciating the role of DNA methylation

Dr. Mendelson's team evaluated blood samples from 7,800 men and women who were participating in the Framingham Heart Study, Lothian Birth Cohort, and 3 other population-based studies. They looked for DNA methylation markers at numerous sites in the genome, then looked to determine if the markers differed depending on BMI—and if those differences fit any predictable pattern.

"We looked at 480,000 sites of DNA methylation from blood-derived DNA in relation to BMI," Dr. Mendelson said. "We found 83 sites where methylation differed in relation to BMI." Those sites were located on 62 different genes.

The methylation was linked with differences in the expression of genes involved in both energy balance and lipid metabolism, the researchers reported.

Participants’ blood was scored based on the number of methylation changes identified. The more changes found, the higher the BMI of the individual. The score on methylation captured 18 percent of the variation in BMI when tested in a separate population.2

For each standard deviation (SD) increase in the methylation measure in age- and sex-adjusted models, the researchers found the odds ratio for obesity (BMI > 30) and overweight (BMI of 25 - 29.9) as compared to the reference group (BMI < 25) were 2.8 (95% CI 2.3-3.5; p=1.6x 10-25) and 1.9 (95% CI 1.6-2.2; p=2.5 x 10-18), respectively.1

When the researchers focused on differences in methylation at one gene, SREBF1, they found it was linked with undesirable lipid levels, elevated blood glucose ranges associated with diabetes, and a greater risk for cardiovascular disease. This gene encodes for a known regulator of lipid metabolism, Dr. Mendelson said.

Despite the strength of the findings, the researchers wrote that "the cross sectional nature of the data limits definitive causal determination." They also said that ''evidence is accumulating those epigenetic modifications, such as DNA methylation, are related to obesity-related diseases in the general population."

Further study is needed to tease out exactly who is at risk of developing obesity and obesity-related conditions based on gene expression. "Using BMI at a population level is very good at estimating risk on average," Dr. Mendelson told EndocrineWeb, but it is not as efficient on an individual basis.

The question to be answered, he says, is "can we use epigenetic profiles in your blood to better understand who is at risk?"

Understanding that, according to Dr. Mendelson, may pave the way for the development of therapies to truly individualize prevention and treatment of excessive, undesirable weight gain.

Clinical perspective on epigenetics, obesity

"We know obesity is much more than just calories in, calories out," says Priyathama Vellanki, MD, assistant professor of endocrinology, metabolism and lipids, Emory University School of Medicine and a member of the Endocrine Web editorial board. The new research,1 she said, ''may eventually help us find out what is controlling the genes that cause obesity. This study didn't exactly show causality," she said, but it did offer a clearer understanding of the multiple factors influencing the development of obesity and concomitant diseases. 

This study introduces the concept that obesity occurs not just because of variations in genes from person to person, but also because of the way these genes are expressed or not, Dr. Vellanki told EndocrineWeb. "There have been many genome-wide association studies," she said, "yet, they don't explain all the heritability we see with obesity, or with diabetes." That would be the newest information for most physicians, she said.

Eventually, she agreed, it may be possible to design treatments targeted at specific pathways affected by methylation on an individual level. And, with that the research may provide allow us to customize nutrition advice based on individual genetic risk, said Dr. Vellanki. "Epigenetic changes are also very dependent on micronutrients," she said. Methylation can respond to different nutrients.

While the study advances our understanding of the factors driving obesity in some individuals but not others, it's too soon to give advice to patients based on this research, Dr. Vellanki said. Hopefully, she said, these findings will lead to more functional studies that shed light on what is going on in adipose tissue and muscles, for instance.

Findings such as these, she says, are ''going to take us closer to precision medicine.''

Neither clinician indicated any conflicts of interest with regard to the study.

To read the full study, click here: PLOS.

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