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

We investigated whether deleterious mutations in MC4R contribute to obesity in Mexican children and adults.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.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.