The Melanocortin 4 Receptor p.Ile269Asn Mutation Is Associated with Childhood and Adult Obesity in Mexicans

The Melanocortin 4 Receptor p.Ile269Asn Mutation Is Associated with Childhood and Adult Obesity in Mexicans

Abstract Context Rare partial/complete loss-of-function mutations in the melanocortin-4 receptor (MC4R) gene are the most common cause of Mendelian obesity in European populations, but their contribution to obesity in the Mexican population is unclear. Objective and Design We investigated whether de...

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Published in:The journal of clinical endocrinology and metabolism Vol. 105; no. 4; pp. e1468 - e1477
Main Authors: Vázquez-Moreno, Miguel, Zeng, Helen, Locia-Morales, Daniel, Peralta-Romero, Jesús, Asif, Hamza, Maharaj, Arjuna, Tam, Vivian, Romero-Figueroa, María D S, Sosa-Bustamante, Gloria P, Méndez-Martínez, Socorro, Mejía-Benítez, Aurora, Valladares-Salgado, Adan, Wacher-Rodarte, Niels, Cruz, Miguel, Meyre, David
Format: Journal Article
Language:English
Published: US Oxford University Press 01-04-2020
Copyright Oxford University Press
Subjects:
Adult
Adults
Amino acids
Biomarkers - analysis
Body Mass Index
Child
Children
Female
Follow-Up Studies
Genetic Predisposition to Disease
Genotype
Humans
Isoleucine
Male
Melanocortin
Melanocortin MC4 receptors
Mexico - epidemiology
Middle Aged
Mutation
Obesity
Obesity - epidemiology
Obesity - genetics
Obesity - pathology
Pedigree
Phenotype
Population
Prognosis
Receptor, Melanocortin, Type 4 - genetics
Mexico
mutation
Mexican population
children
obesity
adults
melanocortin
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Summary:Abstract Context Rare partial/complete loss-of-function mutations in the melanocortin-4 receptor (MC4R) gene are the most common cause of Mendelian obesity in European populations, but their contribution to obesity in the Mexican population is unclear. Objective and Design We investigated whether deleterious mutations in MC4R contribute to obesity in Mexican children and adults. Results We provide evidence that the MC4R p.Ile269Asn (rs79783591) mutation may have arisen in modern human populations from a founder event in native Mexicans. The MC4R Isoleucine 269 is perfectly conserved across 184 species, which suggests a critical role for the amino acid in MC4R activity. Four in silico tools (SIFT, PolyPhen-2, CADD, MutPred2) predicted a deleterious impact of the p.Ile269Asn substitution on MC4R function. The MC4R p.Ile269Asn mutation was associated with childhood (Ncontrols = 952, Ncases = 661, odds ratio (OR) = 3.06, 95% confidence interval (95%CI) [1.94–4.85]) and adult obesity (Ncontrols = 1445, Ncases = 2,487, OR = 2.58, 95%CI [1.52–4.39]). The frequency of the MC4R p.Ile269Asn mutation ranged from 0.52 to 0.59% and 1.53 to 1.59% in children and adults with normal weight and obesity, respectively. The MC4R p.Ile269Asn mutation co-segregated perfectly with obesity in 5 multigenerational Mexican pedigrees. While adults with obesity carrying the p.Ile269Asn mutation had higher BMI values than noncarriers, this trend was not observed in children. The MC4R p.Ile269Asn mutation accounted for a population attributable risk of 1.28% and 0.68% for childhood and adult obesity, respectively, in the Mexican population. Conclusion The MC4R p.Ile269Asn mutation may have emerged as a founder mutation in native Mexicans and is associated with childhood and adult obesity in the modern Mexican population.
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content type line 23
ISSN:0021-972X
1945-7197
DOI:10.1210/clinem/dgz276