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


METHODS
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.


CONCLUSIONS
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.
Cole
Shelley A
SA
Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA.
Butte
Nancy F
NF
Voruganti
V Saroja
VS
Cai
Guowen
G
Haack
Karin
K
Kent
Jack W
JW
Blangero
John
J
Comuzzie
Anthony G
AG
McPherson
John D
JD
Gibbs
Richard A
RA
D000328:Adult; D001066:Appetite / Q000235:genetics*; D015992:Body Mass Index; D049628:Body Size; D002648:Child; D002887:Chromosomes, Human, Pair 18; D002149:Energy Intake; D004734:Energy Metabolism / Q000235:genetics*; D015444:Exercise; D005091:Exons; D005190:Family; D014644:Genetic Variation; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008019:Life Style; D015810:Linkage Disequilibrium / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D050177:Overweight / Q000453:epidemiology / Q000235:genetics; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*
C470072:MC4R protein, human; D035683:MicroRNAs; D044105:Receptor, Melanocortin, Type 4