Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI del Instituto Mexicano del Seguro Social, Ciudad de México, México.
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
J Clin Endocrinol Metab. 2020 Apr 1;105(4). doi: 10.1210/clinem/dgz276.
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.
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 = 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.
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.
黑皮质素-4 受体（MC4R）基因的罕见部分/完全功能丧失突变是欧洲人群中孟德尔肥胖的最常见原因，但它们对墨西哥人群肥胖的贡献尚不清楚。
我们研究了 MC4R 中的有害突变是否导致墨西哥儿童和成人肥胖。
我们提供的证据表明，MC4R p.Ile269Asn（rs79783591）突变可能是由于墨西哥原住民的一个奠基者事件而在现代人类群体中出现的。MC4R 中的异亮氨酸 269 在 184 个物种中完全保守，这表明该氨基酸在 MC4R 活性中起着关键作用。四种计算机工具（SIFT、PolyPhen-2、CADD、MutPred2）预测 p.Ile269Asn 取代对 MC4R 功能具有有害影响。MC4R p.Ile269Asn 突变与儿童肥胖（对照组=952，病例组=661，比值比（OR）=3.06，95%置信区间（95%CI）[1.94-4.85]）和成人肥胖（对照组=1445，病例组=2487，OR=2.58，95%CI [1.52-4.39]）相关。MC4R p.Ile269Asn 突变在体重正常和肥胖的儿童和成人中的频率分别为 0.52%至 0.59%和 1.53%至 1.59%。MC4R p.Ile269Asn 突变在 5 个墨西哥多代家族中与肥胖完全共分离。虽然携带 p.Ile269Asn 突变的肥胖成年人的 BMI 值高于非携带者，但这种趋势在儿童中并未观察到。MC4R p.Ile269Asn 突变导致墨西哥人群中儿童肥胖的人群归因风险为 1.28%，成人肥胖的人群归因风险为 0.68%。
MC4R p.Ile269Asn 突变可能是在墨西哥原住民中出现的一个奠基者突变，与现代墨西哥人群中的儿童和成人肥胖有关。
