Human Molecular Genetics Advance Access originally published online on May 21, 2007
Human Molecular Genetics 2007 16(15):1837-1844; doi:10.1093/hmg/ddm132
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Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene
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, Germany, 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 Klinik Lindberg, Winterthur, Switzerland, 10 INSERM Pediatrics Endocrinology and U561, Saint Vincent de Paul Hospital, Paris V University, Paris, France and 11 Department of Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
* To whom correspondence should be addressed at: Department of Genomic Medicine, Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 0NN, UK. Tel: +44 02083833989; Email: p.froguel{at}imperial.ac.uk
Received April 2, 2007; Revised May 3, 2007; Accepted May 10, 2007
The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for 
2% of obesity cases, but its role in common obesity is still elusive. We analyzed the contribution of non-synonymous mutations V103I (rs2229616, c.307G > A) and I251L (no rs, c.751A > C) to obesity in 16 797 individuals of European origin from nine 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 [odds ratio (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 eight out of nine 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 toward 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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