Everyone knows someone who eats whatever they want and stays thin. A genetic study of more than a million people has now put an unusually precise number on one version of that: roughly 1 in 7,000 people carry a rare mutation that switches off a single copy of a gene called FNIP1, and those carriers show a metabolic profile most people would envy.
They have lower body fat, more lean mass, less liver fat, lower blood sugar, and around 60% lower odds of developing coronary artery disease, type 2 diabetes, or metabolic liver disease. The findings appeared in Nature on August 5 from a team led by the Regeneron Genetics Center.
The twist is what happens when both copies of the same gene are broken. That is not an advantage. It is a serious inherited disease.
A Blood Ratio Most People Never Hear About
The researchers did not go looking for a leanness gene. They went looking at a number sitting in millions of ordinary lab results: the ratio of triglycerides to HDL cholesterol, or TG:HDL.
That ratio turns out to be a compact readout of the body's energy state. As co-author Luca Lotta of the Regeneron Genetics Center told Nature's news team, "The higher this ratio is, the higher the risk of metabolic disease." In the study's epidemiological analysis, a higher ratio was associated with more visceral and total fat, more fat in the liver and skeletal muscle, higher liver enzymes, more biopsy-confirmed liver inflammation and scarring, higher fasting insulin, higher HbA1c, higher blood pressure, and higher inflammation. It also predicted future type 2 diabetes, heart attack, fatty liver disease, and cirrhosis. Those patterns held across African, admixed American, East Asian, South Asian, and European ancestry groups.
So the team sequenced the protein-coding genome in 1,032,116 people across 11 cohorts in North America, Europe, and Asia, and asked which rare variants moved that ratio. Sixty genes cleared the exome-wide threshold, and 59 held up as independent signals, heavily concentrated in liver and fat tissue. Three-quarters were new, and 23 of them, 39%, already encode approved or clinical-stage drug targets. The associations were replicated in the All of Us Research Program, with 114,942 participants.
One Broken Copy Looks Like a Metabolic Advantage
FNIP1 stood out. Eighty-six distinct ultra-rare variants that truncate the FNIP1 protein contributed to the signal, with a combined frequency of 0.01%, and carriers averaged about half a standard deviation lower TG:HDL ratio. In a genetic study, that is a large effect.
The gene encodes folliculin-interacting protein 1, which partners with folliculin to put a brake on mitochondrial activity and energy expenditure. Break one copy, and the brake is weaker.
Across the full dataset, carriers showed lower atherogenic blood lipids, lower body mass index, a more favorable visceral-to-hip-and-thigh fat ratio, less body fat, more lean mass, lower HbA1c, lower liver fat, and lower liver enzymes. In an analysis of 227,636 cases and 265,114 controls, the odds of a combined cardiometabolic disease outcome were 61% lower, with a wide confidence interval ranging from 31% to 78%.
The researchers followed the genetics into the laboratory. Silencing FNIP1 in primary human liver cells switched on genes for fat breakdown and lysosomal activity. In mice fed a high-fat, high-fructose diet, shutting the pathway down in the liver curbed weight gain, cut liver fat, and improved insulin sensitivity.
Not everything translated cleanly. Knocking down Fnip1 alone in mouse liver had no effect on weight gain. Protection appeared only when Fnip1 was disabled together with its paralogue Fnip2, or when folliculin itself was targeted, which the authors attribute to species differences.
Two Broken Copies Cause a Serious Disease
Here is the part that complicates any simple "lucky gene" story. Among the 86 variants driving the protective signal was one already known to cause immunodeficiency-93, an autosomal recessive condition marked by absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy.
In other words, the same genetic change that appears beneficial in one copy causes a serious syndromic immune disorder when inherited from both parents. The study found no significant link between single-copy carriers and that clinical picture, consistent with recessive inheritance.
A related caution shows up next door in the pathway. Carriers of a single loss-of-function variant in FLCN, which encodes FNIP1's partner protein, had an 18-fold higher risk of collapsed lung and a 9-fold higher risk of kidney cancer, the hallmarks of Birt-Hogg-Dubé syndrome. Their metabolic profile trended favorably too, just weaker.
From Genetic Curiosity to Drug Target
None of this is a finding anyone can act on. These are associations in people born with the variant, not evidence that the same effect can be acquired, and body weight remains driven overwhelmingly by environment, behavior, and many genes acting together rather than any single one.
What the work does is nominate a drug target. Because FNIP1 and FLCN are expressed in liver cells, and because hepatocyte-targeted siRNA drugs are already approved for several conditions, the authors argue that selectively silencing FNIP1 in the liver could capture the metabolic benefit while avoiding the consequences of shutting down the pathway body-wide.
That question remains unsettled, and the paper notes this, underscoring the need for future work to clarify both efficacy and safety in humans. One recent mouse study found liver injury and cancer risk after knocking out Flcn in liver cells, a finding the authors address directly rather than around, noting that their own experiments showed a protective liver phenotype and that liver cancer has not been reported in people with two broken copies of FNIP1. No FNIP1-targeting drug exists, and no human has been given one.
The commercial context matters as well. Most of the authors, including the corresponding author, are affiliated with Regeneron, a company with a direct interest in the target.
Anyone concerned about liver fat, blood sugar, or cholesterol should work through those numbers with a clinician rather than reading their own genetics into a study of population averages.
Key Questions Answered
What did the study find?
Rare variants that disable one copy of FNIP1, present in about 1 in 7,000 people sequenced, were associated with lower body fat, lower liver fat, lower blood sugar, more favorable fat distribution and roughly 60% lower odds of cardiometabolic disease.
How large was the study?
Exome sequencing in 1,032,116 people across 11 cohorts on three continents, with replication in 114,942 All of Us participants.
Does this prove the gene causes leanness?
No. These are genetic associations, supported by cell and mouse experiments. Body weight is shaped by many genes, as well as environment and behavior, and no single variant determines it.
Is a broken FNIP1 gene always good?
No. When both copies are disabled, the result is immunodeficiency-93, a recessive disorder involving absent B cells and hypertrophic cardiomyopathy.
Could this become a medicine?
Possibly. The authors propose liver-targeted silencing, following approved siRNA drugs. Safety is unresolved, and one mouse study found liver injury after disabling the partner gene Flcn.
Should anyone get tested for this variant?
There is no clinical reason to. No treatment or guidance follows from carrying it, and the variant is too rare to appear in routine testing.
