title: Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene.
abstract: The melanocortin-4 receptor (MC4R) gene pathogenic mutations are the most prevalent forms of monogenic obesity, responsible for approximately 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.
authors.affiliation: CNRS-8090-Institute of Biology, Pasteur Institute, Lille, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Stutzmann
authors.forename: Vincent
authors.initials: V
authors.lastname: Vatin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cauchi
authors.forename: Anita
authors.initials: A
authors.lastname: Morandi
authors.forename: Béatrice
authors.initials: B
authors.lastname: Jouret
authors.forename: Olfert
authors.initials: O
authors.lastname: Landt
authors.forename: Patrick
authors.initials: P
authors.lastname: Tounian
authors.forename: Claire
authors.initials: C
authors.lastname: Levy-Marchal
authors.forename: Raffaella
authors.initials: R
authors.lastname: Buzzetti
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pinelli
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Fritz
authors.initials: F
authors.lastname: Horber
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougnères
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: David
authors.initials: D
authors.lastname: Meyre
mesh_terms: D000293:Adolescent; D000328:Adult; D015992:Body Mass Index; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*
chemical_list: D044105:Receptor, Melanocortin, Type 4