Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children.

TitleEvidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children.
Publication TypeJournal Article
Year of Publication2010
AuthorsCole, SA, Butte, NF, V Voruganti, S, Cai, G, Haack, K, Kent, JW, Blangero, J, Comuzzie, AG, McPherson, JD, Gibbs, RA
JournalAm J Clin Nutr
Volume91
Issue1
Pagination191-9
Date Published2010 Jan
ISSN1938-3207
KeywordsAdult, Appetite, Body Mass Index, Body Size, Child, Chromosomes, Human, Pair 18, Energy Intake, Energy Metabolism, Exercise, Exons, Family, Genetic Variation, Genotype, Hispanic Americans, Humans, Life Style, Linkage Disequilibrium, MicroRNAs, Obesity, Overweight, Parents, Polymorphism, Single Nucleotide, Receptor, Melanocortin, Type 4
Abstract

BACKGROUND: Melanocortin-4-receptor (MC4R) haploinsufficiency is the most common form of monogenic obesity; however, the frequency of MC4R variants and their functional effects in general populations remain uncertain.OBJECTIVE: The aim was to identify and characterize the effects of MC4R variants in Hispanic children.DESIGN: MC4R was resequenced in 376 parents, and the identified single nucleotide polymorphisms (SNPs) were genotyped in 613 parents and 1016 children from the Viva la Familia cohort. Measured genotype analysis (MGA) tested associations between SNPs and phenotypes. Bayesian quantitative trait nucleotide (BQTN) analysis was used to infer the most likely functional polymorphisms influencing obesity-related traits.RESULTS: Seven rare SNPs in coding and 18 SNPs in flanking regions of MC4R were identified. MGA showed suggestive associations between MC4R variants and body size, adiposity, glucose, insulin, leptin, ghrelin, energy expenditure, physical activity, and food intake. BQTN analysis identified SNP 1704 in a predicted micro-RNA target sequence in the downstream flanking region of MC4R as a strong, probable functional variant influencing total, sedentary, and moderate activities with posterior probabilities of 1.0. SNP 2132 was identified as a variant with a high probability (1.0) of exerting a functional effect on total energy expenditure and sleeping metabolic rate. SNP rs34114122 was selected as having likely functional effects on the appetite hormone ghrelin, with a posterior probability of 0.81.CONCLUSION: This comprehensive investigation provides strong evidence that MC4R genetic variants are likely to play a functional role in the regulation of weight, not only through energy intake but through energy expenditure.

DOI10.3945/ajcn.2009.28514
Alternate JournalAm. J. Clin. Nutr.
PubMed ID19889825
PubMed Central IDPMC2793108
Grant ListR01 DK059264 / DK / NIDDK NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
C06 RR13556 / RR / NCRR NIH HHS / United States
C06 RR017515 / RR / NCRR NIH HHS / United States
MH59490 / MH / NIMH NIH HHS / United States
R01 DK080457 / DK / NIDDK NIH HHS / United States
DK59264 / DK / NIDDK NIH HHS / United States