Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use.

Autor:	Le Collen L; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France; Department of Clinical Genetic, University Hospital Center of Reims, Reims, France; University of Lille, Lille, France. Electronic address: lle-collen@chu-reims.fr., Delemer B; Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France., Poitou C; Assistance Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France; Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches Research Unit (NutriOmics), Paris, France., Vaxillaire M; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; University of Lille, Lille, France., Toussaint B; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; University of Lille, Lille, France., Dechaume A; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; University of Lille, Lille, France., Badreddine A; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; University of Lille, Lille, France., Boissel M; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; University of Lille, Lille, France., Derhourhi M; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; University of Lille, Lille, France., Clément K; Assistance Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France; Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches Research Unit (NutriOmics), Paris, France., Petit JM; Department of Endocrinology Diabetology, University Hospital Central of F. Mitterrand Dijon-Bourgogne, Dijon, France., Mau-Them FT; Unité Fonctionnelle Innovation en Diagnostic Génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France; INSERM UMR1231 GAD, Dijon, France., Bruel AL; Unité Fonctionnelle Innovation en Diagnostic Génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France; INSERM UMR1231 GAD, Dijon, France., Thauvin-Robinet C; Unité Fonctionnelle Innovation en Diagnostic Génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France; INSERM UMR1231 GAD, Dijon, France; Centre de Référence Maladies Rares 'Anomalies du développement et syndromes malformatifs,' Centre de Génétique, FHU TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France., Saveanu A; Aix-Marseille University, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France; Assistance Publique Hôpitaux de Marseille, Reference Center for Rare Pituitary Diseases HYPO, Marseille, France; Assistance-Publique des Hôpitaux de Marseille, Laboratory of Molecular Biology, Conception Hospital, Marseille, France., Cherifi BG; CHU Bordeaux, Endocrinology, Diabetology & Nutrition, Bordeaux, France; University of Bordeaux, Bordeaux, France; INSERMU1215 Neurocentre Magendie, University of Bordeaux, Bordeaux, France., Le Beyec-Le Bihan J; Assistance Publique Hôpitaux de Paris, Endocrine and Oncological Biochemistry Department, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France; INSERM U1149, Centre de recherche sur l'inflammation, Paris, France., Froguel P; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; University of Lille, Lille, France; Department of Metabolism, Imperial College London, London, United Kingdom., Bonnefond A; Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France; University of Lille, Lille, France; Department of Metabolism, Imperial College London, London, United Kingdom. Electronic address: amelie.bonnefond@inserm.fr.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2023 Jul; Vol. 25 (7), pp. 100857. Date of Electronic Publication: 2023 Apr 21.
DOI:	10.1016/j.gim.2023.100857
Abstrakt:	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. 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. 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. 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. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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