Sophie Courbage1,2, Christine Poitou3,2, Johanne Le Beyec-Le Bihan4, Alexandra Karsenty1, Julie Lemale1, Véronique Pelloux2, Jean-Marc Lacorte4, Jean-Claude Carel5, Nathalie Lecomte5, Caroline Storey5, Gianpaolo De Filippo5,6, Muriel Coupaye3,7, Jean-Michel Oppert3, Patrick Tounian1,2, Karine Clément3,2, Béatrice Dubern1,2. 1. Assistance Publique-Hôpitaux de Paris (AP-HP), Reference Centre for Rare Diseases (PRADORT, Prader-Willi Syndrome and other Rare Forms of Obesity with Eating Behavior Disorders), Pediatric Nutrition and Gastroenterology Department, Armand-Trousseau Hospital, Sorbonne University, Paris, France. 2. Sorbonne Université, INSERM, Nutrition and Obesities; Systemic Approaches (NutriOmics) Research Unit, Paris, France. 3. Assistance Publique-Hôpitaux de Paris (AP-HP), Reference Centre for Rare Diseases (PRADORT, Prader-Willi Syndrome and other Rare Forms of Obesity with Eating Behavior Disorders), Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France. 4. Assistance Publique-Hôpitaux de Paris (AP-HP), Endocrine and Oncological Biochemistry Department, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France. 5. Université de Paris, F-75019, Paris, France; AP-HP.Nord Université de Paris. Hôpital Universitaire Robert-Debré, Service d'Endocrinologie Diabétologie Pédiatrique F-75019, Paris, France. 6. Assistance Publique-Hôpitaux de Paris (AP-HP), Bicêtre Hospital, Medicine for Adolescents Department, Le Kremlin-Bicêtre, France. 7. Assistance Publique-Hôpitaux de Paris (AP-HP), Explorations Fonctionnelles Department, Louis-Mourier Hospital, Centre Intégré Nord Francilien de l'Obésité (CINFO) and Université de Paris, Centre de Recherche sur l'Inflammation, Inserm UMRS 1149, Paris, France.
Abstract
CONTEXT: Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established. OBJECTIVE: To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. METHODS: In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. RESULTS: The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI. CONCLUSION: Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.
CONTEXT: Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established. OBJECTIVE: To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. METHODS: In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. RESULTS: The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI. CONCLUSION: Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.
Authors: Alejandro Campos; Lizeth Cifuentes; Anas Hashem; Bradley Busebee; Maria D Hurtado-Andrade; Maria L Ricardo-Silgado; Alison McRae; Alan De la Rosa; Fauzi Feris; Joshua T Bublitz; Donald Hensrud; Michael Camilleri; Todd A Kellogg; Jeanette E Eckel-Passow; Janet Olson; Andres Acosta Journal: Obes Surg Date: 2022-06-03 Impact factor: 3.479