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

Author： Stutzmann Fanny Vatin Vincent Cauchi Stphane Morandi Anita Jouret Batrice Landt Olfert Tounian Patrick Levy-Marchal Claire Buzzetti Raffaella Pinelli Leonardo Balkau Beverley Horber Fritz Bougnres Pierre Froguel Philippe Meyre David

Publisher： Oxford University Press

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.16, Iss.15, 2007-08, pp. : 1837-1844

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Abstract

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 16797 individuals of European origin from nine independent casecontrol, population-based and familial cohorts. We observed a consistent negative association of I251L variant (prevalence ranging 0.411.21) 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.