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

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.

Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations

“…In the present study, we did not observe a baseline difference between carriers and noncarriers for any of these traits, which is in line with studies using similar sampling designs [ 11 , 14 , 16 , 17 ]. Specifically, we did not observe a baseline difference for BMI and BFMI, an important result suggesting that among children with obesity, those with and without MC4R -induced obesity cannot be easily distinguished in the general population—a discovery that has been made by several other teams previously [ 4 , 7 , 49 ]. In contrast, among adults with obesity, carriers of MC4R mutations are heavier than their noncarrier counterparts [ 4 , 7 ], indicating that MC4R -induced obesity leads to a more severe phenotype in adulthood.…”

“…Specifically, we did not observe a baseline difference for BMI and BFMI, an important result suggesting that among children with obesity, those with and without MC4R -induced obesity cannot be easily distinguished in the general population—a discovery that has been made by several other teams previously [ 4 , 7 , 49 ]. In contrast, among adults with obesity, carriers of MC4R mutations are heavier than their noncarrier counterparts [ 4 , 7 ], indicating that MC4R -induced obesity leads to a more severe phenotype in adulthood. Lower SBP and/or DBP have been reported for individuals with loss-of-function MC4R mutations compared with noncarriers [ 10 ].…”

“…The number of identified MC4R mutations exceeds 369 [ 2 , 3 ], and MC4R deleterious mutations are responsible for an autosomal co-dominant form of monogenic obesity [ 4 ]. While the prevalence of carriers of MC4R mutations varies with ethnicity [ 5 – 7 ], up to 2% carry damaging mutations in MC4R among samples of non-consanguineous individuals with obesity of European descent, making MC4R deficiency the most common form of monogenic obesity [ 4 ]. Based on studies including children with damaging MC4R mutations, specific characteristics have been associated with MC4R deficiency, namely increased fat and lean mass, increased linear growth, increased bone mineral density, hyperphagia, and hyperinsulinemia [ 8 , 9 ].…”

Abordaje nutrigenómico de la obesidad: ¿dónde estamos?

“…Debido a la presencia de muchas variantes con efectos leves a moderados sobre la susceptibilidad a obesidad, se han desarrollado los puntajes de riesgo genético (GRS, por sus siglas en inglés), que examinan los efectos cumulativos de las SNV en interacciones dietarías y susceptibilidad a enfermedades (11) . Variantes en otros genes como los del receptor 4 de la melanocortina (MC4R) así como en los pertenecientes a la familia de apolipoproteínas (APOB, APOA1 y APOC3) que están relacionados con la regulación del consumo de alimentos y el metabolismo de los lípidos, respectivamente, han sido asociados a complicaciones de la obesidad como la diabetes mellitus tipo 2 y el síndrome metabólico (23)(24)(25)(26) .…”

Eating behaviour in contrasting adiposity phenotypes: Monogenic obesity and congenital generalized lipodystrophy

“…33,115 Mutations in MC4R represent the commonest cause of human monogenic/oligogenic obesity, with a prevalence of about less than 2% in patients with obesity, being this estimation highly dependent on ethnicity and founder effects (published range: 0.2%-5.6%). 31,52,115,[119][120][121] It is also possible that MC4R mutations also provide incomplete penetrance on appetite traits in MC4R carriers versus noncarriers, as proposed in studies using eating behaviour scores from the Three-Factor Eating Questionnaire (TFEQ (Table 1). 28,128 In all CGL cases, the inability to store triglycerides in adipocytes is associated with ectopic hepatic and muscle fat accumulation, which is the likely cause of the severe insulin resistance and early-onset diabetes seen in these patients.…”