title: Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children.
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.
  
  
  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.
authors.affiliation: Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA.
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Butte
authors.forename: V Saroja
authors.initials: VS
authors.lastname: Voruganti
authors.forename: Guowen
authors.initials: G
authors.lastname: Cai
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
authors.forename: John D
authors.initials: JD
authors.lastname: McPherson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
mesh_terms: 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*
chemical_list: C470072:MC4R protein, human; D035683:MicroRNAs; D044105:Receptor, Melanocortin, Type 4