Scientists from the Regeneron Genetics Center (RGC) have discovered rare genetic mutations in the GPR75 gene that are associated with protection against obesity.
As part of the research that led to the finding, published in Science, RGC scientists analyzed deidentified genetic and associated health data from 645,000 volunteers from the United Kingdom, United States and Mexico, including participants in Geisinger’s MyCode Community Health Initiative.
It is estimated that more than one billion people will be suffering from severe obesity (body mass index [BMI] of 35 or higher) by 2030. Working with collaborators, RGC scientists found that individuals who have at least one inactive copy of the GPR75 gene have lower BMI and, on average, tend to weigh about 12 pounds less and face a 54% lower risk of obesity than those without the mutation. Protective mutations were found in about one of every 3,000 people sequenced.
“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, D.O., director for 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. Further studies and evaluation are needed to determine if reducing weight in this manner can also lower the risk of conditions commonly associated with high BMI, such as heart disease, diabetes, high blood pressure and fatty liver disease.”
Regeneron scientists, collaborating with scientists at New York Medical College, replicated their finding in mice that were genetically engineered using Regeneron’s VelociGene® technology to lack copies of the GPR75 gene. Such mice gained 44% less weight than mice without the mutation when both groups were fed a high-fat diet. Regeneron scientists are pursuing multiple therapeutic pathways – such as antibody, small molecule and gene silencing approaches – based on this newly discovered genetic target.
“Discovering protective genetic superpowers, such as in GPR75, provides hope in combatting global health challenges as complex and prevalent as obesity,” said George D. Yancopoulos, M.D., Ph.D., co-founder, president and chief scientific officer at Regeneron. “Discovery of protective mutations – many of which have been made by the Regeneron Genetics Center in its eight-year history – 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.”
Reference: Parsa Akbari et al., “Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity”, Science 02 Jul 2021: Vol. 373, Issue 6550, eabf8683 DOI: https://doi.org/10.1126/science.abf8683
Provided by Geisinger