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Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children^1,2,3,4

¹ From the Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX (SAC, VSV, KH, JWK, JB, and AGC); the USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX (NFB); the SAS Institute, Cary, NC (GC); the Cancer Genomics, Ontario Institute for Cancer Research, Toronto, Canada (JDM); and the Human Genome Sequencing Center, Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX (RAG).

² The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

³ Supported by the National Institutes of Health (DK59264 and MH59490), and the USDA/ARS (Cooperative Agreement 58-6250-51000-037). Work performed at the Southwest Foundation for Biomedical Research in San Antonio, TX, was conducted at facilities constructed with support from the Research Facilities Improvement Program of the National Center for Research Resources, National Institutes of Health (C06 RR13556 and C06 RR017515).

⁴ Address correspondence to NF Butte, Baylor College of Medicine USDA/ARS Children’s Nutrition Research Center, 1100 Bates Street, Houston, TX 77030. E-mail: nbutte{at}bcm.edu.

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.

Received for publication August 10, 2009. Accepted for publication October 12, 2009.