| Title | Non synonymous polymorphisms in Melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. | | Author(s) | Stutzmann F, Vatin V, Cauchi S, Morandi A, Jouret B, Landt O, Tounian P, Levy-Marchal C, Buzzetti R, Pinelli L, Balkau B, Horber F, Bougnères P, Froguel P, Meyre D | | Institution | CNRS-8090-Institute of Biology, Pasteur Institute, Lille, France. | | Source | Hum Mol Genet 2007 May 21. | | Abstract | 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 17519222 |
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