# Towards Precision Medicine in Obesity: Genetic Copy Number Variations Profiling Linked to Specific Metabolic Dysregulation Patterns

## TL;DR

This study explores how genetic copy number variations in obesity-related genes are linked to specific metabolic issues, suggesting potential for personalized obesity treatments.

## Contribution

The study identifies specific CNVs in obesity-related genes and links them to distinct metabolic dysregulation patterns in individuals with elevated adipose tissue.

## Key findings

- 11.86% of participants showed genetic alterations in obesity-related genes, with some duplications linked to higher insulin and HOMA-IR levels.
- Duplications in SEZ6L2-1 and SH2B1-2 were associated with a reduced trunk adipose tissue percentage but not BMI, suggesting leptin signaling modulation.
- Genetic profiles revealed complex associations between CNVs and obesity phenotypes, indicating potential for early risk stratification and personalized interventions.

## Abstract

This study aimed to identify and analyse the copy number variations (CNVs) in the genes involved in the pathophysiology of obesity and correlate these findings with the phenotypic manifestations. Genetic screening of 59 apparently healthy individuals with elevated adipose tissue percentages was performed, assessing the duplications and deletions of obesity-related genes through the MLPA (Multiplex Ligation-dependent Probe Amplification) technique. Clinical and metabolic parameters, including insulin, HOMA-IR, leptin, and adiponectin levels, were measured to better describe the obesity profiles of the participants in this study. In our research, 11.86% of the subjects presented with genetic alterations in obesity-associated genes, with 16% of these modifications involving concurrent duplications in SEZ6L2-1 and SH2B1-2, linked to doubled insulin and tripled HOMA-IR levels. However, the same duplications were associated with a reduced trunk adipose tissue percentage (but not BMI), suggesting leptin signalling modulation. Duplications were more frequent in the metabolically unhealthy obese patients, resulting in a higher relative risk of an obese metabolically unhealthy diagnosis (1.85-fold increased risk in subjects with SEZ6L2-1/SH2B1-2 duplications, p = 0.52). No duplications or deletions were reported in the non-obese patient groups, defined according to the BMI criteria. A partial LEPR deletion was identified in one patient, associated with severe insulin resistance (second-highest HOMA-IR in the cohort). Another subject presented with 11 duplications (7 in LEPR) and reported the lowest adiponectin and second-highest leptin levels among the genetically altered subjects. The genetic profiles revealed complex associations between the CNVs and obesity phenotypes, highlighting the potential for early risk stratification. Despite the interpretative challenges, identifying the genetic predispositions could significantly predict cardiometabolic risk and be used to map personalised interventions to possibly modulate phenotypic expression.