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

2019; Oxford University Press; Volume: 105; Issue: 4 Linguagem: Inglês

10.1210/clinem/dgz276

1945-7197

Miguel Vázquez‐Moreno, Helen Zeng, Daniel Locia‐Morales, Jesús Peralta‐Romero, Hamza Asif, Arjuna Maharaj, Vivian Tam, María del Socorro Romero-Figueroa, Gloria Patricia Sosa-Bustamante, Socorro Méndez‐Martínez, Aurora Mejía‐Benítez, Adán Valladares‐Salgado, Niels H. Wacher, Andrea Socorro Álvarez Villaseñor, Kelly G Acosta, Raquel Flores-Torrecillas, Uriel Flores-Osuna, Mariell G García-Avilés, Roxana González‐Dzib, René A Gameros-Gardea, María Luisa Pizano-Zárate, Jorge A. Núñez-Hernández, Verónica de León-Camacho, Roberto Karam-Araujo, Perla Corona-Salazar, Fernando Suárez‐Sánchez, Jaime Gómez-Zamudio, Eugenia Flores‐Alfaro, Arturo Reyes-Hernández, Catalina Peralta-Cortázar, Emmanuel G Martínez-Moralesvalla, Luz V Díaz de León Morales, Irma L del C González-González, Arturo Maximiliano Reyes-Sosa, Sonia Lazcano-Bautista, María Georgina Arteaga-Alcaraz, Nandy García-Silva, Moisés Herrera-Lemus, Gress Marissell Gómez Arteaga, Anel Gómez‐García, Martha V Urbina-Treviño, Diana Carolina Villalpando Sánchez, Cleto Álvarez-Aguilar, Ramón Ernesto Jiménez-Arredondo, Martha I. Dávila‐Rodríguez, Francisco González‐Salazar, Laura Hermila de la Garza-Salinas, Aleyda Pérez‐Herrera, Jorge Martínez-Torres, Elizabeth Méndez-Fernández, Víctor A. Segura-Bonilla, Mariana Gutiérrez-Hernández, Lilia Susana Gallardo-Vidal, Leticia Blanco Castillo, José J. García-González, Julio Medina‐Serrano, Adrian Canizalez‐Román, Cruz Mónica López-Morales, Jaime Valle-Leal, Martin Segura-Chico, Rafael Violenté-Ortiz, Verónica Fernández-Jiménez, Norma A Sánchez-Hernández, Miguel Cruz, David Meyre,

Genetic Associations and Epidemiology

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.