Gene Mutations Linked to More Muscle, Less Belly Fat, and Broad Health Benefits

A large-scale genomic study has linked variants in the FNIP1 gene to a healthier metabolic profile, including a higher proportion of muscle, lower levels of belly fat and blood sugar, and a reduced risk of diseases such as type 2 diabetes and heart disease¹.

The FNIP1 gene helps regulate cellular metabolism and allows cells to sense and respond to key nutrients. Only around one in 7,000 people whose genomes were analysed carried one of the newly identified FNIP1 variants associated with these potential health benefits, researchers report today in Nature.

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For the millions of people who do not carry these rare genetic variants, the findings could still have important implications. They point to FNIP1 as a potential drug target that might one day help mimic some of the variants’ protective effects against cardiometabolic disease. This group of interconnected conditions includes stroke, diabetes, heart attack and certain forms of liver disease.

Cardiometabolic diseases “are the number one cause of death in the world, and they have a strong genetic basis”, says Luca Lotta, a human geneticist at the Regeneron Genetics Center in Tarrytown, New York, and a co-author of the study.

Study of one million genomes reveals FNIP1 link

To investigate the biological mechanisms behind cardiometabolic disease, Lotta and his team used advanced DNA sequencing to analyse the genomes of more than one million people from diverse populations across three continents. The researchers searched for genetic variants associated with changes in a blood biomarker known as the TG:HDL ratio. This measures the level of triglycerides — a type of blood fat — relative to high-density lipoprotein (HDL) cholesterol, often called ‘good’ cholesterol. “The higher this ratio is, the higher the risk of metabolic disease,” says Lotta.

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One gene stood out: FNIP1. People carrying certain mutations that inactivate one of the two copies of the gene had significantly healthier metabolic profiles than the wider population. On average, they also had a 60% lower risk of cardiometabolic disease.

The researchers then tested these genetic findings in human liver cells by silencing FNIP1 and related genes. This increased the activity of genes involved in breaking down lipids, or fats. In follow-up experiments in mice, the researchers found that the same approach helped protect against disease, providing further evidence that targeting FNIP1 could have therapeutic potential.