Rare genetic variants protect against obesity, study says


    Sixteen rare genetic variants could protect people from being obese, a new study claims. 

    Researchers performed ‘whole exome sequencing’ – an extensive genetic test that looks at thousands of genes at once – on more than 645,000 people. 

    They identified 16 variants that influence body mass index (BMI), the standard measurement for determining if people are of a normal weight, overweight or obese. 

    Rare genetic mutations in one of the genes, called GPR75, was associated with protection against obesity. 

    People with at least one inactive copy of GPR75 weighed about 12 pounds less and faced a 54 per cent lower risk of obesity than those without the mutation. 

    Carriers of the mutation had a 1.9 kg/m2 lower BMI on average – an almost two point reduction. 

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    Being overweight or obese results in about 2.8 million deaths a year, according to the World Health Organisation (WHO). Pictured, an obese woman

    Being overweight or obese results in about 2.8 million deaths a year, according to the World Health Organisation (WHO). Pictured, an obese woman 

    The findings provide potential therapeutic targets for treating obesity in humans, according to the team.

    Obesity to is linked to a variety of human diseases, including diabetes, cancer and heart disease. 

    The study was led by researchers at Regeneron, a New York-based biotechnology firm. 

    ‘Discovering protective genetic superpowers, such as in GPR75, provides hope in combating global health challenges as complex and prevalent as obesity,’ said George D. Yancopoulos, president and chief scientific officer at Regeneron. 

    ‘Discovery of protective mutations will allow us to unlock the full potential of genetic medicine.’   

    BMI is a measure of body fat based on your weight in relation to your height. If you have a BMI of 30 or more, you are obese. 

    It’s already known that body fat is a ‘highly heritable trait’, and that genetic factors play an essential role in energy balance and body fat regulation. 

    One of the 16 genes, expressed in the brain and called GPR75, showed the strongest association to lower BMI

    One of the 16 genes, expressed in the brain and called GPR75, showed the strongest association to lower BMI


    The human genome consists of 3 billion nucleotides or ‘letters’ of DNA. 

    But only a small percentage – 1.5 per cent – of those letters are actually translated into proteins, the functional players in the body. 

    The ‘exome’ consists of all the genome’s exons, which are the coding portions of genes.  

    Source: Broad Institute  

    But how genes and rare coding variants can predispose or protect individuals from obesity is not fully understood. 

    Understanding this could provide a pathway to developing safe and effective therapeutic strategies for treating obesity. 

    For their study, the team sequenced the exomes of 645,626 individuals from the UK, the US and Mexico.

    The ‘exome’ is the portion of DNA that contains a person’s 22,000 genes.

    It only represents 1 per cent of the genome but contains most key information for diagnosing inherited conditions. 

    GPR75 – a brain-expressed G protein-coupled receptor – was observed in roughly four out of every 10,000 sequenced people. 

    It showed the strongest association to lowering BMI out of all 16, according to Regeneron.

    Researchers validated the finding in mice that were genetically engineered to lack copies of the GPR75 gene. 

    Such mice gained 44 per cent less weight than mice without the mutation when both groups were fed a high-fat diet.    

    The study has been published in the journal Science, along with an accompanying perspective piece by Giles Yeo and Stephan O’Rahilly, two University of Cambridge researchers who were not involved. 

    ‘The principles of discovery exemplified in the study of Akbari et al. go beyond that of body weight control and obesity,’ they write.

    ‘It is likely that human exome sequencing at scale will become an increasingly important entry point for the discovery of mechanistic insights into mammalian biology.’ 

    Recent studies revealed 1.9 billion adults worldwide are overweight (with a BMI of between 25 and 29.9) and 650 million are obese (with a BMI of 30 or more). 

    Being overweight or obese results in about 2.8 million deaths a year, according to the World Health Organisation (WHO). 

    It is also estimated about 57 per cent of the world’s adult population will be overweight or obese by 2030.


    A record one million people were admitted to hospital because of obesity in England in 2020, official data has shown.

    Data released by NHS Digital shows admissions for conditions caused by obesity or where obesity affected people’s treatment rose by 17 per cent in the year 2019 to 2020.

    Women made up almost two thirds (64 per cent) of the hospital cases and admissions were more common in poorer areas than wealthy places.

    The medical director of NHS England, Professor Stephen Powis, called the figures ‘shocking’ and said they were ‘a growing sign of the nation’s obesity crisis’.

    He said obese people were putting themselves at risk of cancer, heart disease and stroke and also putting extra pressure on the NHS, which spends billions of pounds every year on treating people for their weight. 

    People were most often admitted to hospital for arthritis in their hips and knees and for heart disease, while others needed treatment directly for their weight.  

    The NHS figures show that around 10,780 admissions were caused directly by obesity — for weight loss or gastric surgery — while the rest were for problems related to obesity.

    But in total there were 1.02 million hospital admissions where someone’s obesity was listed as the main or secondary cause for their visit, up from 876,000 the year before.  

    The most common of these were for appointments during pregnancy, knee and hip arthritis and heart disease.  

    ‘Carrying extra pounds not only puts a strain on your physical health, but also on the health service so as lockdown restrictions start to ease, there has never been a better time to take steps to live a healthier lifestyle,’ Professor Powis said. 


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