Why do some people seem to be prone to weight gain? Obesity has been linked to a variety of genetic changes, yet these differences don’t fully explain the variation in people’s body mass index (BMI). “Even though we’ve genetically sequenced more and more people at greater and greater breadth and depth, we haven’t completely explained who develops obesity and why,” says Michael Mendelson, MD, ScM, a pediatric cardiologist with Boston Children’s Hospital’s Preventive Cardiology Program.
Nor do prior studies explain why some overweight people develop health complications from obesity, like cholesterol problems, diabetes, hypertension and heart disease, while others don’t. Now comes strong evidence that an important factor is DNA methylation — a so-called epigenetic modification that influences whether genes are turned on or off.
“Unlike your DNA sequence, these regulatory modifications change over time and can influence your risk of disease in later life,” says Mendelson, also a research fellow in the Population Sciences Branch of the National Heart Lung and Blood Institute (NHLBI).
In one of the largest efforts to date, Mendelson and Riccardo Marioni of the University of Edinburgh systematically looked for markers of DNA methylation at more than 400,000 sites in the genome, together with collaborators from the NHLBI, the Harvard School of Public Health and the Framingham Heart Study. Testing blood samples from 7,800 adults from five population studies, including the Framingham Heart Study and the Lothian Birth Cohort, they looked to see if these markers differed according to BMI in a predictable pattern.
As reported today in PLoS Medicine, obesity indeed correlated with widespread methylation changes — at 83 locations in 62 different genes. These, in turn, were associated with differences in the expression of genes involved in energy balance and lipid metabolism and with an increased risk for weight-related health problems such as coronary artery disease.
An additive effect
The more methylation changes people in the study had, the greater their BMI. Tallied into a methylation score and tested in a separate population, the changes captured 18 percent of people’s variation in BMI. For each standard deviation increase in the score, the odds ratio for obesity was 2.8 times higher.
Applying Mendelian randomization, a statistical technique that can get at whether an association is causal, the researchers concluded that 16 of the 83 identified genomic sites were differently methylated as a result of obesity. This finding that held true across people of different ethnicities.
“This study may help us understand the molecular mechanism linking obesity to metabolic risk,” says co-author Daniel Levy, MD. He directs the Framingham Heart Study, which is supported by the NHLBI. “That knowledge may pave the way for new approaches to prevent even more dire complications such as cardiovascular disease.”
Potential treatment targets, biomarkers
A difference in methylation at one gene, SREBF1, appeared to be causative of obesity and was clearly linked with unhealthy blood lipid profiles, glycemic traits (a risk factor for diabetes) and coronary artery disease. SREBF1 encodes a known regulator of lipid metabolism and could be a target for a drug treatment, the researchers believe.
“Taken together, these results suggest that epigenetic modifications may help identify therapeutic targets to prevent or treat obesity-related disease in the population,” says Mendelson. “The next step is to understand how we can modify epigenetic modifications to prevent the development of cardiometabolic disease.”
With further study, methylation markers in the blood could be easily accessible biomarkers to guide such therapy, he adds, bringing a “precision medicine” approach to preventive cardiology.