DEVELOPMENT AND PREVENTION OF CHILDHOOD OBESITY
Location: Children Nutrition Research Center (Houston, Tx)
Title: Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children
| Cole, Shelley - |
| Butte, Nancy - |
| Voruganti, V - |
| Cai, Guowen - |
| Haack, Karin - |
| Kent, Jr, Jack - |
| Blangero, John - |
| Comuzzie, Anthony - |
| Mcpherson, John - |
| Gibbs, Richard - |
Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 12, 2009
Publication Date: January 1, 2010
Citation: Cole, S.A., Butte, N.F., Voruganti, V.S., Cai, G., Haack, K., Kent, Jr, J.W., Blangero, J., Comuzzie, A.G., Mcpherson, J.D., Gibbs, R.A. 2010. Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children. American Journal of Clinical Nutrition. 91(1):191-199.
Interpretive Summary: Obesity is a complex disease caused by both genetic and environmental factors. In humans, mutations in the melanocortin-4-receptor (MC4R) gene are the most common form of obesity, caused by a change in DNA sequence. The aim of this study was to identify mutations in MC4R contributing to obesity among 1016 Hispanic children. We identified 7 rare mutations in the coding region and 18 mutations in nearby regions of MC4R that were associated with body size, body fat, fasting glucose, several hormones (insulin, leptin and ghrelin), as well as energy expenditure, physical activity, and food intake. Our novel findings support a role for MC4R mutations in the regulation of body weight through food intake and physical activity in Hispanic children.
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. The aim of this study was to identify and characterize the effects of MC4R variants in Hispanic children. 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. 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. This comprehensive investigation provides strong evidence that MC4R genetic variants are likely to play a functional role in the regularion of weight, not only through energy intake, but also through energy expenditure.