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Genetic Study of the Melanin-Concentrating Hormone Receptor 2 in Childhood and Adulthood Severe Obesity

Centre National de la Recherche Scientifique Unité Mixte de Recherche 8090-Institute of Biology (M.G., V.V., C.L., C.S., C.W., P.F., D.M.), Pasteur Institute, 59000 Lille, France; Myriad Genetics Incorporated (V.A., A.Y.), Salt Lake City, Utah; Institut National de la Santé et de la Recherche Médicale U780-IFR69 (B.H.), Paris XI University Villejuif, 94800 Villejuif, France; Institut National de la Santé et de la Recherche Médicale U563 (M.T.), Children’s Hospital, 31000 Toulouse, France; Department of Pediatric Gastroenterology and Nutrition (P.T.), Trousseau Hospital, 75012 Paris, France; Institut National de la Santé et de la Recherche Médicale U557/Institut National de la Recherche Agronomique U1125 (S.H.), L’Institut Scientifique et Technique de la Nutrition et de l’Alimentation, 75003 Paris, France; Pediatric Endocrine Unit (J.W.), Jeanne de Flandre Hospital, 59000 Lille, France; Institut National de la Santé et de la Recherche Médicale Units 457 and 690 (C.L.-M.), Robert Debre Hospital, 75019 Paris, France; Institut National de la Santé et de la Recherche Médicale Pediatrics Endocrinology and U561 (C.L.S., P.B.), Saint Vincent de Paul Hospital, Paris V University, 75014 Paris, France; and Genomic Medicine (P.F.), Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom

Address all correspondence and requests for reprints to: Philippe Froguel, P. Section of Genomic Medicine, Hammersmith Hospital, Du Cane Road, Imperial College London, London W12 0NN, United Kingdom. E-mail: p.froguel{at}imperial.ac.uk.

Context: The melanin-concentrating hormone receptor 2 (MCHR2) is a G protein-coupled receptor for melanin-concentrating hormone, a neuropeptide that plays an important role in feeding behaviors. MCHR2 maps on chromosome 6q16.3, in a susceptibility locus for childhood obesity.

Objective: The aim of this study was to investigate the association between MCHR2 variation and human obesity.

Design: Case control and family-based studies were performed.

Participants: A total of 141 obese children and 24 nonobese adult subjects was sequenced, and case-control analyses were conducted using 628 severely obese children and 1401 controls.

Results: There were 11 single nucleotide polymorphisms (SNPs) identified. We showed nominal association among –38,245 ATG A/G SNP (P = 0.03; 95% confidence interval 1.02–1.34; odds ratio 1.17), A76A T/C SNP (P = 0.03; 95% confidence interval 0.58–0.97; odds ratio 0.75), and childhood obesity. Analysis of 645 trios with childhood obesity supported further the A76A T/C association, showing an overtransmission to obese children of the at risk T allele (59.0%; P = 0.01), especially in children with most severe forms of obesity (Z score of body mass index > 4) (67.0%; P = 0.003). The A76A at risk T allele was also associated with overeating during meals (P = 0.02) in an additional group of 102 nonobese children. None of the MCHR2 variants, including the A76A SNP, showed association with adult severe obesity, although a trend for association of the T allele of this variant with food disinhibition (P = 0.06) and higher hunger (P = 0.09) was found. This variant was not associated with childhood obesity in an independent case-control study, including 1573 subjects (P = 0.98). Moreover, the A76A SNP did not explain the linkage on the 6q locus.

Conclusion: Our results altogether suggest that MCHR2 is not a major contributor to polygenic obesity and support a modest effect of the A76A SNP on food intake abnormalities in childhood.

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