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.:

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The melanocortin 4 receptor p.Ile269Asn mutation is associated with childhood and adult obesity in Mexicans.

J Clin Endocrinol Metab. 2019 Dec 16;:

Authors: Vázquez-Moreno M, Zeng H, Locia-Morales D, Peralta-Romero J, Asif H, Maharaj A, Tam V, Romero-Figueroa MDS, Sosa-Bustamante GP, Méndez-Martínez S, Mejía-Benítez A, Valladares-Salgado A, Wacher-Rodarte N, National Obesity Network Mexico, Cruz M, Meyre D

Abstract

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=1,445, Ncases=2,487, OR=2.58, 95%CI [1.52-4.39]). The frequency of the MC4R p.Ile269Asn mutation ranged from 0.52-0.59% and 1.53-1.59% in children and adults with normal weight and obesity, respectively. The MC4R p.Ile269Asn mutation co-segregated perfectly with obesity in five multigenerational Mexican pedigrees. While adults with obesity carrying the p.Ile269Asn mutation had higher BMI values than non-carriers, 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.

PMID: 31841602 [PubMed - as supplied by publisher]