Rare genetic variant may protect against obesity, provide new drug target
Click Here to Manage Email Alerts
People with a rare genetic coding variant that occurs in approximately 1 in 3,000 people had lower BMI and 54% lower odds for obesity compared with those who were not heterozygous carriers, data published in Science show.
In an exome-wide discovery analysis, researchers sequenced 640,000 exomes and identified 16 genes for which the burden of rare, protein-coding variants was associated with BMI at exome-wide statistical significance, including associations at five brain-expressed G protein-coupled receptors: CALCR, MC4R, GIPR, GPR151 and GPR75. Protein-truncating variants in GPR75 — found in four of 10,000 sequenced people — were associated with a 1.8 kg/m2 lower BMI, 5.3 kg lower body weight and 54% lower odds for obesity in heterozygous carriers. GPR75 may serve as a viable therapeutic target for obesity. The study was conducted by the Regeneron Genetics Center in collaboration with Geisinger Health System, New York Medical College, the Nuffield department of population health at the University of Oxford and the National Autonomous University of Mexico, using data from the Mexico City Prospective Study, Geisinger’s MyCode Community Health Initiative and UK Biobank.
Healio spoke with Luca A. Lotta, MD, PhD, head of cardiovascular, metabolic and musculoskeletal therapeutic area genetics at Regeneron Genetics Center, and Christopher D. Still, DO, director of the Geisinger Obesity Research Institute, about the value of whole-exome sequencing, new drugs that may mimic the variant, and what the discovery means for future obesity research.
Healio: What led you and your colleagues to undertake this study?
Still: Alongside colleagues at Regeneron Genetics Center, the Nuffield department of population health at the University of Oxford and the National Autonomous University of Mexico, we wanted to better understand the influence of genetics on obesity — to help advance the existing medical and scientific dialogue around obesity’s risk factors, which tends to focus on “nurture,” that is, behavioral and environmental aspects, vs. nature. With current projections of more than 1 billion people living with obesity, defined as a BMI of at least 30 kg/m² by 2030, this represents an urgent health need. The study that led to the discovery of GPR75 is just one that will unlock the clues needed to expand the current scope of interventions for obesity.
Lotta: Obesity is influenced by the environment we live in, diet and physical activity, but several studies have also shown a strong genetic component. We were interested in using whole-exome sequencing on a massive scale to better understand the biology that underlies obesity and pathways that could be modified for therapeutic benefit in people with obesity.
Healio: How does whole exome sequencing work, and what could its potential value be in obesity medicine?
Lotta: The exome is essentially the protein coding region of the genome. You can view it as the sum of all genes in the genome. Exome sequencing is, in practice, akin to genome sequencing, but it ignores the non-protein coding region of the genome that we understand less well. It is focusing on something we feel has the greatest potential for understanding biological pathways implicated in disease.
Healio: For this project, more than 640,000 exomes were sequenced. What did you and your colleagues discover?
Still: We found that individuals who have at least one inactive copy of the GPR75 gene have lower BMI, weigh 12 lb less, on average, and also face a 54% lower risk for obesity than those without the mutation. Protective “loss of function” mutations were found in about one of every 3,000 people sequenced. While extremely rare, these mutations offer a way for drug developers to mimic the impact through the development of new therapeutics.
Lotta: We sequenced the exomes of people from different parts of the world: Mexico, the United Kingdom and the United States. We looked at the association with BMI of rare variants in the protein coding region of the genome. We did not just look at people who were obese. We looked at distribution of body weight and BMI across the entire set of people sequenced. You need scale to study these rare variants, because they can occur 1 in 100 or 1 in 1,000, or in our case, 1 in 3,000. It is an extremely rare occurrence. To make this type of statistical association analysis, you need hundreds of thousands of people.
We found 16 genes where rare variants are associated with higher or lower BMI, hence, higher or lower risk for obesity. There were five G protein-coupled receptors expressed in the brain; among these genes, was a novel gene that had not been linked to obesity before, GPR75. Individuals with this rare variant [have] half the risk for obesity than people without this variant, so this is a protective genetic variant for obesity.
Healio: What could this discovery potentially mean for therapeutics for obesity?
Lotta: The idea is this protective phenotype provides insight that we may be able to modulate this pathway for clinical benefit if we could copy the protective effects of this variant with a medicine. At this point, it has less implication for people who carry this variant. We also collaborated with researchers to better understand how this gene works and introduced a mutation akin to the ones we found in humans in mice. Compared with mice who did not have this mutation on both copies of the gene, those with the mutation gained 44% less weight after having a high-fat diet. This is further validation of our human genetic findings, implicating this gene in energy balance.
Healio: What more do we still need to learn?
Still: By discovering protective mutations such as GPR75, we will be closer to unlocking the full potential of genetic medicine to inform the development of future treatments. These approaches hold great promise for those of us committed to improving the lives and health of the millions of people affected.
Lotta: We are interested in understanding how this new pathway we found works and how it relates to other pathways shown to affect the risk for obesity and ways we can modulate this pathway for benefit. We are also interested in understanding the biology of several other genes that we found, their relevance to obesity risk and other cardiovascular or metabolic diseases.
More generally, we want to apply this massive-scale sequencing of the exome to other obesity-related disease and other disease at large, to find these “golden nuggets” hidden in the human genome, if you will, which make people resistant to disease.
Reference:
Akbari P, et al. Science. 2021;doi:10.1126/science.abf8683.
Collapse
Read more about
Click Here to Manage Email Alerts