Geneticists Discover Gene Mutations That Protect Against Obesity

Individuals with at least one inactive copy of the gene have lower BMIs and, on average, face a 54% lower risk of obesity than individuals without the mutations.

Researchers have identified rare mutations in the GPR75 gene that protect against obesity, according to new findings published in Science.

The genetics of approximately 650,000 individuals were sequenced to find the gene mutations, using novel technologies and approaches. The findings provide new insights into the genetic basis of obesity and could lead to potential therapeutics that mimic these genetic “superpowers,” according to a press release from Regeneron Pharmaceuticals. More than 1 billion people could have obesity, which is defined as a body mass index (BMI) of 30 or higher, by 2030.

“Discovering protective genetic superpowers, such as in GPR75, provides hope in combating global health challenges as complex and prevalent as obesity,” said George D. Yancooulos, MD, PhD, president and chief scientific officer at Regeneron, in the press release. “Discovery of protective mutations…will allow us to unlock the full potential of genetic medicine by instructing on where to deploy cutting-edge approaches like gene-editing, gene-silencing, and viral vector technologies.”

Investigators found that individuals who have at least 1 inactive copy of the GPR75 gene have lower BMIs and, on average, tend to weigh approximately 12 pounds less and face a 54% lower risk of obesity than individuals without the mutation. These protective mutations were found in approximately 1 in every 3000 people sequenced, according to the press release.

To investigate this further, a research team analyzed deidentified genetic and associated health data from 645,000 volunteers from the United Kingdom, United States, and Mexico. The study used data from the Mexico City Prospective Study, Geisinger’s MyCode Community Health Initiative, and UK Biobank.

Researchers then validated the finding in mice that were genetically engineered to lack copies of the GPR75 gene. These mice gained 44% less weight than mice without the mutation when both groups were fed a high-fat diet.

“This is a potentially game-changing discovery that could improve the lives and health of millions of people dealing with obesity, for whom lasting interventions have often been elusive,” said Christopher D. Still, DO, director of the Geisinger Obesity Research Institute at Geisinger Medical Center. “While the behavioral and environmental ties to obesity are well understood, the discovery of GPR75 helps us put the puzzle pieces together to better understand the influence of genetics.”

Still concluded that more studies are needed to determine whether reducing weight in this manner can also reduce the risk of common conditions associated with obesity, including heart disease, diabetes, high blood pressure, and fatty liver disease. To investigate this, researchers are pursuing multiple therapeutic approaches to target GPR75, including through antibodies, small molecules, and gene silencing.

REFERENCE

Regeneron Genetics Center Discovers GPR75 Gene Mutations That Protect Against Obesity. News release. July 1, 2021. July 7, 2021. https://investor.regeneron.com/index.php/news-releases/news-release-details/regeneron-genetics-center-discovers-gpr75-gene-mutations-protect