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Genetic Variant Found that Predisposes People to Slimness Carried by 60% of Europeans

Researchers from the Spanish National Cancer Research Centre (CNIO) and the IMDEA Food Institute have discovered that those who have a certain version of a gene involved in cell nutrition tend to accumulate less fat.

But “this association does not mean that people with this genetic variant can overeat without getting fat,” says Alejo Efeyan (CNIO), senior co-author of the paper together with Ana Ramirez de Molina (IMDEA Food).

The work is published in Genome Biology. It represents a breakthrough in the understanding of the genetic components of obesity, which may pave the way to future anti-obesity treatments, the authors say.

How much do genes influence our body weight? For the general population this influence is estimated in 20%, according to studies that in recent years have analysed the complete genome of tens of thousands of individuals. In other words, “lifestyle, such as eating habits and exercise, have a great impact, but genetic factors also exert an influence,” explains researcher Nerea Deleyto-Seldas from the Spanish National Cancer Research Centre (CNIO).

Some of these genetic factors are already known. Nearly a hundred genetic variants that moderately increase the probability of having a high Body Mass Index (BMI, a common indicator of being overweight or suffering from obesity) have already been identified. CNIO and IMDEA Food researchers have identified a new one. Their work is published in the journal Genome Biology, with Nerea Deleyto-Seldas (CNIO) and Lara P. Fernandez, from the IMDEA Food Institute, as first co-authors.

Genetic variants are slightly different versions of a gene, and most often do not result in visible changes in the body. But this specific variant does: it affects the amount of fat the body stores, and the authors of the new study show that it is particularly prevalent in Europe. It is estimated to be present in almost 60% of the European population.

For Alejo Efeyan, head of the CNIO’s Metabolism and Cell Signalling Group, “the finding is a step forward in the understanding of the genetic components of obesity.” Ana Ramirez de Molina, director of the IMDEA Food Institute, believes that “a deep knowledge of the involvement of the cellular nutrient-sensing pathway in obesity may have implications for the development and application of personalised strategies in the prevention and treatment of obesity.”

Genetics and clinical data from 790 volunteers
Overweight and obesity are defined by an abnormal or excessive accumulation of fat that affects health. To find genetic variants that influence the phenomenon, and the associated metabolic alterations, a team from IMDEA Food Institute collected genetic material and data such as body weight, BMI, total and visceral fat, muscle mass, waist and hip circumferences, among others, from 790 healthy volunteers.

Researchers studied the possible associations of these parameters with 48 genetic variants, selected based on their potential functional relevance. They detected a “significant correlation between one of these variants in the FNIP2 gene and many of these obesity-related parameters,” explains the study, which has just been published in the scientific journal Genome Biology.

Demonstration in animal models
The CNIO team then studied the effect of this variant in mice genetically-engineered to express it. “We found that mice with this variant, which in people is associated with leanness, have between 10% and 15% less fat than their non-carrier counterparts,” explains Efeyan.

In humans, the effect of this variant cannot be isolated from that of the many other genetic and environmental variables that influence the physical constitution, so it is impossible to estimate precisely the strength of its effect. But given that the influence of genetics on obesity does not exceed 20%, the contribution of the variant now identified is necessarily small.

For this reason, researchers use terms like predisposition or tendency: “It is not at all the case that people with this genetic variant can overeat without getting fat,” Efeyan clarifies.

The animals genetically modified for this study showed no other alterations or differences. “The observations in mice are very striking, because many of these studies are typically limited to reporting associations in the human population; in this paper we show that changing a single letter in the entire mouse genome replicates what we observed in the human variant,” Efeyan continues.

Related to what the cell ‘eats’
This variant is present in a gene that participates in a signalling pathway that tells the cell what nutrients are available. Why a small genetic change affects the tendency to be lean now needs to be studied.

The goal for the future is to “better understand the molecular basis of the effects of this genetic variant, i.e. what is happening biochemically to the cell,” adds Nerea Deleyto. “We need to improve the genetic tools to dissect when the functional consequences of this variant are important in the organism, for example, during the fat development,” she stresses.

The finding also raises questions for other areas of science, such as what evolutionary pressures favoured the selection of this variant and when it occurred.

Paper: Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region. Genome Biology; https://doi.org/10.1186/s13059-022-02798-5.

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