Journal Article

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

Fanny Stutzmann, Vincent Vatin, Stéphane Cauchi, Anita Morandi, Béatrice Jouret, Olfert Landt, Patrick Tounian, Claire Levy-Marchal, Raffaella Buzzetti, Leonardo Pinelli, Beverley Balkau, Fritz Horber, Pierre Bougnères, Philippe Froguel and David Meyre

in Human Molecular Genetics

Volume 16, issue 15, pages 1837-1844
Published in print August 2007 | ISSN: 0964-6906
Published online May 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm132
Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene

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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.

Journal Article.  4678 words.  Illustrated.

Subjects: Genetics and Genomics

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