The Melanocortin 4 Receptor p.Ile269Asn Mutation Is Associated with Childhood and Adult Obesity in Mexicans.
J Clin Endocrinol Metab
; 105(4)2020 04 01.
Article
em En
| MEDLINE
| ID: mdl-31841602
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Biomarcadores
/
Predisposição Genética para Doença
/
Receptor Tipo 4 de Melanocortina
/
Mutação
/
Obesidade
Tipo de estudo:
Observational_studies
/
Prognostic_studies
Limite:
Adult
/
Child
/
Female
/
Humans
/
Male
/
Middle aged
País como assunto:
Mexico
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article