Rare gene variants linked to better body fat distribution and metabolic health

Rare variants in the FNIP1 gene are linked to lower body fat, less liver fat, a more favourable fat distribution and around 60 percent lower odds of cardiometabolic disease, according to the largest exome-sequencing study of energy metabolism to date.

The study, published in Nature, analysed the protein-coding regions of DNA in 1,032,116 people from 11 cohorts across North America, Europe and Asia. The team focused on the ratio of triglycerides to HDL cholesterol – a blood marker associated with metabolic health and the risk of conditions including type 2 diabetes and coronary artery disease. Of 59 genes found to be associated with this ratio, FNIP1 showed some of the strongest effects across multiple metabolic traits.

'The higher this ratio is, the higher the risk of metabolic disease,' said Dr Luca Lotta of Regeneron Pharmaceuticals in Tarrytown, New York, who co-led the study. 'These individuals consume, store and utilise energy more than individuals without those mutations, and that is the protective factor.' Dr Lotta added that evolutionary pressures may help explain why such variants are so rare, as conserving calories efficiently may have been advantageous for much of human history.

Roughly one in 7000 people carry an ultra-rare protein-truncating variant in FNIP1 – a genetic change predicted to disrupt the gene's function. Only 155 participants in the study carried such a variant. Carriers had lower triglyceride-to-HDL ratios, lower body mass index, less visceral fat around the organs, lower liver fat and lower blood sugar levels, alongside around 60 percent lower odds of a combined cardiometabolic disease outcome encompassing coronary artery disease, type 2 diabetes and liver disease.

FNIP1 encodes folliculin-interacting protein 1, which interacts with folliculin and AMP-activated protein kinase and is involved in regulating cellular metabolism and energy use. Experiments provided evidence that disrupting the pathway can alter lipid metabolism: silencing FNIP1 in primary human liver cells increased the expression of genes involved in lipid breakdown and lysosomal function. In mice, however, the effects were more complex: combined disruption of Fnip1 and its related gene Fnip2, or disruption of Flcn, protected against diet-induced weight gain, reduced liver triglycerides and improved insulin sensitivity, whereas disruption of Fnip1 or Fnip2 alone did not protect against weight gain.

The findings come with important caveats. Complete FNIP1 deficiency caused by disruption of both copies of the gene is associated with a rare inherited disorder involving immunodeficiency and cardiomyopathy. The current study found favourable metabolic associations among people carrying a single predicted loss-of-function variant, but this does not establish that long-term therapeutic inhibition of FNIP1 would be safe. Related variants in FLCN, which encodes folliculin, cause Birt-Hogg-Dubé syndrome, an inherited disorder associated with lung cysts and an increased risk of kidney tumours.

The researchers proposed the FNIP1-FLCN pathway as a potential therapeutic target, noting that gene-silencing therapies directed at the liver are already used to treat some metabolic conditions. They stopped short of claiming this approach would replicate the effects of GLP-1 drugs – the mechanisms differ fundamentally. Further work is needed to establish whether deliberately inhibiting FNIP1 in humans would be safe and effective.