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Updated: Jun 7, 2025
09:34
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
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Monoallelic pathogenic variants in LEPR do not cause obesity.
Jérôme Delplanque1, Lauriane Le Collen2, Hélène Loiselle1
1Inserm/CNRS UMR 1283/8199, Institut Pasteur de Lille, EGID, Lille University Hospital, Lille, France; University of Lille, Lille, France.
American Journal of Human Genetics
|November 19, 2024
Summary
Heterozygous pathogenic leptin receptor (LEPR) variants do not increase obesity risk or body mass index (BMI). Functional assessments and large-scale data confirm no association, questioning setmelanotide use in such cases.
Area of Science:
- Genetics
- Metabolic Disorders
- Pharmacology
Background:
- Biallelic pathogenic LEPR variants cause obesity treatable with setmelanotide.
- Heterozygous LEPR variants' impact on obesity is not fully understood.
- A clinical trial investigates setmelanotide for obesity in individuals with heterozygous LEPR variants.
Purpose of the Study:
- To functionally assess heterozygous LEPR variants.
- To evaluate the association of these variants with obesity and BMI.
Main Methods:
- Sequencing of LEPR in ~10,000 participants (French RaDiO study).
- In vitro functional assays (luciferase, western blot) for 86 rare heterozygous variants.
- Analysis of exome data from 200,000 individuals (UK Biobank) and literature review.
Main Results:
- 12 pathogenic heterozygous LEPR variants identified using ACMG criteria.
- No association found between pathogenic heterozygous LEPR variants and obesity or BMI.
- Literature data and UK Biobank analysis corroborated the lack of association.
Conclusions:
- Monoallelic pathogenic LEPR variants do not elevate obesity risk or BMI.
- Findings challenge the use of setmelanotide solely based on heterozygous LEPR variants.
- Further evaluation is needed regarding the clinical utility of setmelanotide in this population.
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