Melanocortin-4 receptor pathway dysfunction in obesity: Patient stratification aimed at MC4R agonist treatment.

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Melanocortin-4 receptor pathway dysfunction in obesity: Patient stratification aimed at MC4R agonist treatment.

J Clin Endocrinol Metab. 2018 May 02;:

Authors: Ayers KL, Glicksberg BS, Garfield AS, Longerich S, White JA, Yang P, Du L, Chittenden TW, Gulcher JR, Roy S, Fiedorek F, Gottesdiener K, Cohen S, North KE, Schadt EE, Li SD, Chen R, Van der Ploeg LHT

Abstract
Context: The hypothalamic melanocortin 4 receptor (MC4R)-pathway serves a critical role in regulating bodyweight. Loss of function (LoF) mutations in the MC4R pathway including mutations in the POMC (1), PCSK1, LEPR (2) or the MC4R genes (3) have been shown to be causative of early-onset severe obesity.
Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1 and LEPR genes, we sought to estimate the number of US individuals with bi-allelic MC4R pathway LoF variants.
Results: We predict approximately 650 α-MSH/POMC, 8,500 PCSK1 and 3,600 LEPR homozygous and compound heterozygous individuals in the US, cumulatively enumerating over 12,800 MC4R pathway deficient obese patients. Very few of these have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: β-MSH/POMC, PCSK1 N221D, and a novel PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity we tested associations between body-mass index (BMI) and LoF mutation-burden in the POMC, PCSK1 and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway predisposes to a higher BMI than non-carriers or heterozygous LoF carriers with a defect in only one gene.
Conclusions: Our analysis represents a genetically-rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese sub-populations should be studied to understand MC4R agonist (e.g., setmelanotide) treatment responsiveness.

PMID: 29726959 [PubMed - as supplied by publisher]

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