The Melanocortin 4 Receptor p.Ile269Asn Mutation Is Associated with Childhood and Adult Obesity in Mexicans
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 ,   National Obesity Network Mexico, Álvarez-Villaseñor Andrea S , Acosta Kelly G , Flores-Torrecillas Raquel , Flores-Osuna Uriel , García-Avilés Mariell G , González-Dzib Roxana del S , Gameros-Gardea René A , Pizano-Zárate María L , Núñez-Hernández Jorge A , de León-Camacho Verónica , Karam-Araujo Roberto , Corona-Salazar Perla , Suarez-Sánchez Fernando , Gómez-Zamudio Jaime , Flores-Alfaro Eugenia , Reyes-Hernández Arturo , Peralta-Cortázar Catalina , Martínez-Moralesvalla Emmanuel G , Díaz de León Morales Luz V , González-González Irma L del C , Reyes-Sosa Arturo M , Lazcano-Bautista Sonia , Arteaga-Alcaraz María G , García-Silva Nandy , Herrera-Lemus Moisés , Gómez-Arteaga Gress M , Gómez-García Anel , Urbina-Treviño Martha V , Villalpando-Sánchez Diana C , Álvarez-Aguilar Cleto , Jiménez-Arredondo Ramón E , Dávila-Rodríguez Martha I , González-Salazar Francisco , de la Garza-Salinas Laura H , Pérez-Herrera Aleyda , Martínez-Torres Jorge , Méndez-Fernández Elizabeth , Segura-Bonilla Víctor A , Gutiérrez-Hernández Mariana , Gallardo-Vidal Lilia S , Blanco-Castillo Leticia , García-González José J , Medina-Serrano Julio M , Canizalez-Román Adrián , López-Morales Cruz M , Valle-Leal Jaime G , Segura-Chico Martin , Violenté-Ortiz Rafael , Fernández-Jiménez Verónica , Sánchez-Hernández Norma A , Cruz Miguel , Meyre David 
Published: December 2019

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.