Implication of Heterozygous Variants in Genes of the Leptin-Melanocortin Pathway in Severe Obesity.

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.

• Authors: Sophie Courbage, Christine Poitou, Johanne Le Beyec-Le Bihan, Alexandra Karsenty, Julie Lemale, Véronique Pelloux, Jean-Marc Lacorte, Jean-Claude Carel, Nathalie Lecomte, Caroline Storey, Gianpaolo De Filippo, Muriel Coupaye, Jean-Michel Oppert, Patrick Tounian, Karine Clément, Béatrice Dubern
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 106 Issue 10 Pg. 2991-3006 (09 27 2021) ISSN: 1945-7197 [Electronic] United States
• PMID: 34097736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• LEP protein, human
• LEPR protein, human
• Leptin
• Receptors, Leptin
• Pro-Opiomelanocortin
• PCSK1 protein, human
• Proprotein Convertase 1

Topics

• Adult
• Age of Onset
• Body Mass Index
• Child
• Female
• Genetic Association Studies
• Genetic Variation
• Heterozygote
• Homozygote
• Humans
• Leptin (genetics)
• Male
• Obesity, Morbid (genetics)
• Phenotype
• Pro-Opiomelanocortin (genetics)
• Proprotein Convertase 1 (genetics)
• Receptors, Leptin (genetics)
• Retrospective Studies
• Signal Transduction (genetics)