CLINICAL RESEARCH ARTICLE e1468 J Clin Endocrinol Metab, April 2020, 105(4):e1468–e1477 https://academic.oup.com/jcem doi:10.1210/clinem/dgz276 ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals. permissions@oup.com Received 13 September 2019. Accepted 13 December 2019. First Published Online 16 December 2019. Corrected and Typeset 12 March 2020. The Melanocortin 4 Receptor p.Ile269Asn Mutation Is Associated with Childhood and Adult Obesity in Mexicans Miguel Vázquez-Moreno, 1,2 Helen Zeng, 2 Daniel Locia-Morales, 1 Jesús Peralta-Romero, 1 Hamza Asif, 2 Arjuna Maharaj, 2 Vivian Tam, 2 María D.S. Romero-Figueroa, 3 Gloria P. Sosa-Bustamante, 4 Socorro Méndez-Martínez, 5 Aurora Mejía-Benítez, 2 Adan Valladares-Salgado, 1 Niels Wacher-Rodarte, 6 National Obesity Network Mexico, 7 Miguel Cruz, 1 and David Meyre 2,8 1 Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI del Instituto Mexicano del Seguro Social, Ciudad de México, México; 2 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada; 3 Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud, Universidad Anáhuac, Campus Norte, Huixquilucan, México; 4 Hospital de Gíneco-Pediatría, Instituto Mexicano del Seguro Social León, Guanajuato, México; 5 Coordinación de Investigación en Salud, Instituto Mexicano del Seguro Social Puebla, Puebla, México; 6 Unidad de Investigación en Epidemiología Clínica, Hospital de Especialidades Bernardo Sepúlveda, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México; 7 Instituto Mexicano del Seguro Social México. Investigators listed in the appendix; and 8 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada ORCiD number: 0000-0003-4850-7444 (D. Meyre). 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 (N controls  = 952, N cases  = 661, odds ratio (OR) = 3.06, 95% confdence interval (95%CI) [1.94–4.85]) and adult obesity (N controls  = 1445, N cases  = 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. Downloaded from https://academic.oup.com/jcem/article/105/4/e1468/5679482 by guest on 08 January 2024