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Scientists from the Regeneron Genetics Center® (RGC) have discovered rare genetic mutations in the GPR75 gene associated with protection against obesity. People with these protective mutations have 54% reduced risk of obesity, according to research published today in Science. 

It is estimated that more than one billion people could be suffering from obesity (body mass index [BMI] of 30 or higher) by 2030. Working with collaborators from NDPH, Geisinger Health System, New York Medical College, and the National Autonomous University of Mexico (UNAM), 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. 

The scientists sequenced genetic information from almost 650,000 people to find rare individuals with this genetic ‘superpower,’ providing new insights into the genetic basis of obesity. Protective ‘loss of function’ mutations were found in about one of every 3,000 people sequenced. 

‘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.’ 

As part of the research that led to the finding, RGC scientists analysed deidentified genetic and associated health data from 645,000 volunteers from Mexico, the United Kingdom, and the US. The study used data from the Mexico City Prospective StudyMyCode Community Health Initiative, and UK Biobank

RGC scientists, collaborating with scientists at New York Medical College, then replicated the 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. ‘The discovery of GPR75 is already enabling Regeneron and our collaborators to identify potential ways to safely replicate the effect of this mutation through novel therapeutic approaches,’ said Aris Baras, M.D., Senior Vice President at Regeneron and Head of the Regeneron Genetics Center. ‘This is the latest in a long line of protective human genetics discoveries that have fueled new therapeutics programs at Regeneron. The pace is only quickening, as we uncover more and more about the human genome and work to rapidly translate those discoveries to the development of new medicines.’ 

Professor Jonathan Emberson, UK Principal Investigator for the Mexico City Prospective Study, added ‘This finding demonstrates the benefits of bringing together health and genetic data from studies with large numbers of volunteers. Combining genetic data with other health information enables new insights to emerge that would not have been possible with small numbers of volunteers or single sources of information. This discovery has the potential to improve and prolong the lives of those living with obesity worldwide, and may also enable us to reduce the impact of conditions such as heart disease, diabetes and high blood pressure which are associated with high BMI.’