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

Fanny Stutzmann1, Vincent Vatin, Stéphane Cauchi

  • 1CNRS-8090-Institute of Biology, Pasteur Institute, Lille, France.

Human Molecular Genetics
|May 24, 2007
PubMed

Insights

The melanocortin-4 receptor (MC4R) gene variants I251L and V103I show a protective effect against obesity. These gain-of-function mutations may prevent 2% of obesity cases, highlighting MC4R

Area of Science:

  • Genetics
  • Metabolism
  • Endocrinology

Background:

  • Pathogenic mutations in the melanocortin-4 receptor (MC4R) gene are the leading cause of monogenic obesity, accounting for ~2% of cases.
  • The role of MC4R gene variants in common obesity remains largely undetermined.
  • Understanding MC4R's contribution to obesity is crucial given the rising global obesity rates.

Purpose of the Study:

  • To investigate the contribution of MC4R gene non-synonymous mutations V103I and I251L to obesity risk.
  • To analyze the association of these variants with body mass index (BMI) in diverse populations.
  • To quantify the potential preventive fraction of obesity attributable to these MC4R variants.

Main Methods:

  • Analysis of 16,797 individuals of European origin across nine independent cohorts (case-control, population-based, familial).
  • Genotyping of MC4R variants V103I (rs2229616) and I251L.
  • Statistical analysis including odds ratios (OR) and meta-analyses to assess associations with obesity and BMI.

Main Results:

  • The I251L variant showed a consistent negative association with childhood and adult class III obesity (OR ranging 0.25-0.76) and BMI across eight of nine studies.
  • A modest negative association was observed for the V103I variant with obesity (OR = 0.80, P = 0.002).
  • Meta-analysis confirmed a strong protective effect of I251L (OR = 0.52, P = 3.58x10^-5) and a modest protective effect of V103I.

Conclusions:

  • Gain-of-function mutations I251L and V103I in the MC4R gene may confer protection against obesity.
  • These variants could account for a preventive fraction of obesity similar to that of monogenic MC4R forms (~2%).
  • MC4R signaling tonus plays a significant role in obesity prevention, even in obesogenic environments.

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