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Human Molecular Genetics Advance Access published online on May 21, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm132
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Non synonymous polymorphisms in Melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene

Fanny Stutzmann1, Vincent Vatin1, Stéphane Cauchi1, Anita Morandi2, Béatrice Jouret3, Olfert Landt4, Patrick Tounian5, Claire Levy-Marchal6, Raffaella Buzzetti7, Leonardo Pinelli2, Beverley Balkau8, Fritz Horber9, Pierre Bougnères10, Philippe Froguel1,11,* and David Meyre1

1 CNRS-8090-Institute of Biology, Pasteur Institute, Lille, France 2 Department of Pediatrics, Regional Center for Juvenile Diabetes, University of Verona, Italy 3 INSERM U563, Children's Hospital, Toulouse, France 4 TIB MOLBIOL GmbH, Berlin 5 Department of Pediatric Gastroenterology and Nutrition, Trousseau Hospital, Paris, France 6 INSERM U457, Robert Debré Hospital, Paris, France 7 Endocrinology, Department of Clinical science, La Sapienza University, Roma, Italy 8 INSERM U780-IFR69, University Paris Sud, Villejuif, France 9 Hirslanden Clinic, Zurich, Switzerland 10 INSERM Pediatrics endocrinology and U561, Saint Vincent de Paul Hospital, Paris V University, Paris, France 11 Genomic Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom

Corresponding author: Philippe Froguel, Genomic Medicine, Hammersmith Hospital, Imperial College London, Du Cane Road, London, W12 0NN, United Kingdom. Email: p.froguel{at}imperial.ac.uk, tel: 44 (0)208 383 3989

Received April 2, 2007; Revised May 3, 2007; Accepted May 10, 2007

The melanocortin-4 receptor gene (MC4R) pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for about 2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution to obesity of non synonymous mutations V103I (rs2229616, c.307G>A) and I251L (no rs, c.751A>C), in 16,797 individuals of European origin from 9 independent case-control, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.41-1.21%) with both childhood and adult class III obesity (OR ranging from 0.25 to 0.76, 0.001<p value<0.05), and with modulation of body mass index (BMI) in general populations, in 8 out of 9 studies, whereas only one study showed an association between V103I and BMI. Meta-analyses of previous published data with the current ones provided strong evidence of the protective effect of I251L towards obesity (OR = 0.52, p = 3.58 10-5), together with a modest negative association between V103I and obesity (OR = 0.80, p = 0.002). Taken together, gain-of-function mutations I251L and V103I may be responsible for a preventive fraction of obesity of 2%, which mirrors the prevalence of monogenic obesity due to MC4R haploinsufficiency. These results also emphasize the importance of the MC4R signalling tonus to prevent obesity, even in the context of our current obesogenic environment.


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F. Stutzmann, K. Tan, V. Vatin, C. Dina, B. Jouret, J. Tichet, B. Balkau, N. Potoczna, F. Horber, S. O'Rahilly, et al.
Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees
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