Rare gene variant cuts heart disease risk by 60%
Some people seem naturally protected from metabolic disease. A new study of over one million people now suggests why. A rare mutation in a single gene appears to cut the risk of heart disease and diabetes by as much as 60 percent.
Researchers at biotech company Regeneron analyzed the protein-coding regions of the genome from more than one million people, linked to detailed health records. Rather than starting with a candidate gene, they used the ratio of triglycerides to HDL cholesterol (TG:HDL) as a measure of overall metabolic state. The study was published in Nature.
A higher TG:HDL ratio consistently tracked a worse metabolic profile. People with higher baseline values subsequently developed type 2 diabetes, heart attacks, and liver disease at higher rates. These relationships held across several ancestry groups.
The gene that stood out
The analysis identified 59 genes in which rare protein-altering variants had measurable effects on TG:HDL. One stood out: FNIP1 (folliculin-interacting protein 1). People carrying a specific rare mutation in this gene had a markedly more favorable metabolic profile. Follow-up experiments in human liver cells and mice clarified how this gene regulates energy metabolism, pointing to a potential therapeutic target.
Of the 59 genes identified, 31 are already known drug targets and 23 are already targeted by approved drugs or agents in development. That makes this research practically relevant: for some of these genes, tools to modulate their activity already exist.
What this means for aging
Metabolic dysfunction, the gradual disruption of how the body processes energy, is one of the central processes in aging. Cardiovascular disease, diabetes, and liver disease all increase sharply with age. If a single gene confers a 60 percent lower risk for such conditions, that offers a concrete direction for drug development. The researchers emphasize that further validation is needed before clinical application.
Search terms to explore further: FNIP1 energy metabolism, TG:HDL metabolic risk, rare variant exome association