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

Melanocortin-4 receptor pathway dysfunction in obesity: Patient stratification aimed at MC4R... 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. Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

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Publisher
Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2018-00258
Publisher site
See Article on Publisher Site

Abstract

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. Copyright © 2018 Endocrine Society

Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: May 2, 2018

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