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

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.

[1]  Beverley Balkau,et al.  Variation in FTO contributes to childhood obesity and severe adult obesity , 2007, Nature Genetics.

[2]  M. Jarvelin,et al.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2007, Science.

[3]  Shamil R Sunyaev,et al.  Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. , 2007, American journal of human genetics.

[4]  S. O’Rahilly,et al.  The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals , 2007, International Journal of Obesity.

[5]  D. Lawlor,et al.  Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE , 2007, Human mutation.

[6]  J. Gulcher,et al.  Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution , 2007, Nature Genetics.

[7]  M. Stumvoll,et al.  ENPP1 variants and haplotypes predispose to early onset obesity and impaired glucose and insulin metabolism in German obese children. , 2006, The Journal of clinical endocrinology and metabolism.

[8]  R. Nargund,et al.  Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. , 2006, Journal of medicinal chemistry.

[9]  Zhimin Xiang,et al.  Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. , 2006, Biochemistry.

[10]  P. Boutin,et al.  The INS VNTR locus does not associate with smallness for gestational age (SGA) but interacts with SGA to increase insulin resistance in young adults. , 2006, The Journal of clinical endocrinology and metabolism.

[11]  K. Clément,et al.  Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. , 2006, The Journal of clinical endocrinology and metabolism.

[12]  T. Meitinger,et al.  Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. , 2006, The Journal of clinical endocrinology and metabolism.

[13]  A. Eberle,et al.  Melanocortin-4 Receptor Gene and Complications after Gastric Banding , 2006, Obesity surgery.

[14]  R. Hudson,et al.  An evolutionary framework for common diseases: the ancestral-susceptibility model. , 2005, Trends in genetics : TIG.

[15]  K. Clément,et al.  Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes , 2005, Nature Genetics.

[16]  F. Kronenberg,et al.  Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys , 2005, Journal of Medical Genetics.

[17]  C. Mein,et al.  PPAR-γ2 Pro12Ala Variant Is Associated with Greater Insulin Sensitivity in Childhood Obesity , 2005, Pediatric Research.

[18]  T. Gudermann,et al.  Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. , 2004, American journal of human genetics.

[19]  C. Vaisse,et al.  The human MC4R promoter: characterization and role in obesity. , 2003, Diabetes.

[20]  Thomas Gudermann,et al.  Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. , 2003, The Journal of clinical endocrinology and metabolism.

[21]  F. Horber,et al.  Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. , 2003, The New England journal of medicine.

[22]  Tim Cheetham,et al.  Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. , 2003, The New England journal of medicine.

[23]  Pierre Bougnères,et al.  Genetics of obesity and type 2 diabetes: tracking pathogenic traits during the predisease period. , 2002, Diabetes.

[24]  E. Snyder,et al.  Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort. , 2002, The Journal of clinical endocrinology and metabolism.

[25]  S. Bhattacharyya,et al.  A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. , 2002, Human molecular genetics.

[26]  S. O’Rahilly,et al.  Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. , 2000, The Journal of clinical investigation.

[27]  K. Clément,et al.  Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. , 2000, The Journal of clinical investigation.

[28]  J. Hebebrand,et al.  Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. , 1999, The Journal of clinical endocrinology and metabolism.

[29]  S. Heymsfield,et al.  Identification and functional analysis of novel human melanocortin-4 receptor variants. , 1999, Diabetes.

[30]  J R O'Connell,et al.  PedCheck: a program for identification of genotype incompatibilities in linkage analysis. , 1998, American journal of human genetics.

[31]  T. Aitman,et al.  Molecular screening of the human melanocortin-4 receptor gene: identification of a missense variant showing no association with obesity, plasma glucose, or insulin , 1997, Diabetologia.

[32]  B. Balkau,et al.  [An epidemiologic survey from a network of French Health Examination Centres, (D.E.S.I.R.): epidemiologic data on the insulin resistance syndrome]. , 1996, Revue d'epidemiologie et de sante publique.

[33]  E. Poskitt.  Defining childhood obesity: the relative body mass index (BMI) , 1995, Acta paediatrica.

[34]  T J Cole,et al.  Body mass index reference curves for the UK, 1990. , 1995, Archives of disease in childhood.

[35]  D. Curtis,et al.  Monte Carlo tests for associations between disease and alleles at highly polymorphic loci , 1995, Annals of human genetics.

[36]  T J Cole,et al.  Body Mass Index variations: centiles from birth to 87 years. , 1991, European journal of clinical nutrition.

[37]  O S Miettinen,et al.  Proportion of disease caused or prevented by a given exposure, trait or intervention. , 1974, American journal of epidemiology.