| Title: | Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use |
| Journal: | Genetics in Medicine |
| Published: | 21 Apr 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37092539/ |
| DOI: | https://doi.org/10.1016/j.gim.2023.100857 |
Publication 11368
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Abstract
PURPOSE: Recessive deficiency of proopiomelanocortin (POMC) causes childhood-onset severe obesity. Cases can now benefit from the melanocortin 4 receptor agonist setmelanotide. Furthermore, a phase 3 clinical trial is evaluating setmelanotide in heterozygotes for POMC. We performed a large-scale genetic analysis to assess the effect of heterozygous, pathogenic POMC variants on obesity.</p>
METHODS: A genetic analysis was performed in a family including 2 cousins with childhood-onset obesity. We analyzed the obesity status of heterozygotes for pathogenic POMC variants in the Human Gene Mutation Database. The association between heterozygous pathogenic POMC variants and obesity risk was assessed using 190,000 exome samples from UK Biobank.</p>
RESULTS: The 2 cousins carried a compound heterozygous pathogenic variant in POMC. Six siblings were heterozygotes; only 1 of them had obesity. In Human Gene Mutation Database, we identified 60 heterozygotes for pathogenic POMC variants, of whom 14 had obesity. In UK Biobank, heterozygous pathogenic POMC variants were not associated with obesity risk, but they modestly increased body mass index levels.</p>
CONCLUSION: Heterozygous pathogenic POMC variants do not contribute to monogenic obesity, but they slightly increase body mass index. Setmelanotide use in patients with obesity, which would only be based on the presence of a heterozygous POMC variant, can be questioned.</p>
19 Authors
- Lauriane Le Collen
- Brigitte Delemer
- Christine Poitou
- Martine Vaxillaire
- Bénédicte Toussaint
- Aurélie Dechaume
- Alaa Badreddine
- Mathilde Boissel
- Mehdi Derhourhi
- Karine Clément
- Jean M Petit
- Frédéric Tran Mau-Them
- Ange-Line Bruel
- Christel Thauvin-Robinet
- Alexandru Saveanu
- Blandine Gatta Cherifi
- Johanne Le Beyec-Le Bihan
- Philippe Froguel
- Amélie Bonnefond
1 Application
| Application ID | Title |
|---|---|
| 67575 | Contribution of rare DNA variants to the risk of metabolic disorders and to the level of associated metabolic traits |
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