New Insights Into Genes and Obesity Point to Possible Targets for Treatment

New research reveals association between body mass index and levels of DNA tagging of certain genes. Image: Jeff Morin/

New research suggests that body mass index is linked to differing levels of DNA methylation in the HIF3A gene. Image: Jeff Morin/

Researchers have found that potentially modifiable chemical tagging of a particular gene is associated with obesity in humans, a finding that underscores the complex roots of obesity involving interactions among lifestyle, genetics, and the environment.

Certain genes such as leptin can play a role in obesity, and the increasing use of whole-genome analysis has uncovered dozens of other genes that might contribute to the problem. In mice, studies have also shown that chemical tagging of some genes is linked with obesity. Such tagging, which is influenced by factors in the environment (including the diet), is part of a phenomenon known as epigenetic modification, which affects how genes are expressed by cells. A common type of epigenetic modification is DNA methylation, the reversible addition of a chemical methyl group to parts of DNA. While one’s genetics are predetermined and remain mostly unchanged throughout life (unless a spontaneous mutation occurs), one’s epigenetics are highly dynamic.

Now, a new study released yesterday in The Lancet reveals that DNA methylation of a specific gene involved in oxygen metabolism and energy expenditure in humans appears to be highly linked to body mass index (BMI) in a large population of Europeans.

Scientists at the University of Leicester in England performed genetic analyses on blood samples from 459 individuals of European origin and looked for associations between levels of methylation on various DNA segments and BMI. After searching through the entire DNA sequence, they found 3 segments on 1 gene, HIF3A, which had differing levels of DNA methylation that were significantly correlated with BMI, even after adjustment for other potentially confounding variables.

The researchers found that for every 10% increase in methylation level of these 3 segments of DNA—on a scale from 0 (no methylation) to 100% (full methylation)—BMI increased from 3.2% to 7.8%. In other words, in this particular population, for every 10% increase in HIF3A methylation level, there was an average BMI increase of 0.87 to 2.12 kg/m2.

When the researchers then tested 2 separate populations to see if the results could be replicated (1 group of 339 individuals from France and another group of 1789 individuals from Germany), they found that the associations still held true, although they were less strong. They also tested a fourth group of individuals, using either fat tissue or skin tissue rather than blood. They found an even stronger association between BMI and HIF3A methylation level in fat tissue, but no association in skin tissue.

The authors note that because this was a cross-sectional study, no conclusions about causality can be made. However, they said the findings provide a strong foundation for further research to understand the link between epigenetic changes and obesity, and that understanding the role such changes play could “identify novel therapeutic targets” for this widespread condition.

Categories: Genetics, Nutritional and Metabolic Disorders, Obesity