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Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment
Kristin L Ayers1,2, Benjamin S Glicksberg1, Alastair S Garfield3
1Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
Context:
The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause 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 biallelic MC4R pathway LoF variants.
Results:
We predict ~650 α-melanocyte-stimulating hormone (MSH)/POMC, 8500 PCSK1, and 3600 LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway-deficient obese patients. Few of these variants 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 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 are predisposed to a higher BMI than noncarriers 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 subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.
Insights
Loss of function mutations in the MC4R pathway cause severe obesity. Over 12,800 US individuals may have MC4R pathway deficiencies, impacting body weight regulation and treatment responsiveness.
Area of Science:
- Genetics
- Endocrinology
- Obesity Research
Background:
- The melanocortin 4 receptor (MC4R) pathway is crucial for body weight regulation.
- Loss-of-function (LoF) mutations in POMC, PCSK1, LEPR, or MC4R genes lead to early-onset severe obesity.
Purpose of the Study:
- To estimate the prevalence of biallelic MC4R pathway LoF variants in the US population.
- To analyze the association between MC4R pathway gene variants and body mass index (BMI).
Main Methods:
- Epidemiological analysis of known and predicted LoF variants in POMC, PCSK1, and LEPR genes.
- Statistical association testing between LoF mutation burden and BMI across populations.
Main Results:
- Estimated >12,800 individuals in the US with homozygous or compound heterozygous LoF variants in POMC, PCSK1, or LEPR.
- Individuals with cumulative LoF allele burden in the MC4R pathway exhibit higher BMI compared to non-carriers or single-heterozygous carriers.
Conclusions:
- This study provides a genetic basis for stratifying obese patient subpopulations for MC4R agonist treatment responsiveness.
- Highlights the significant impact of MC4R pathway genetic variants on obesity and potential therapeutic targets.
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