Advertisement

Hormones

, Volume 14, Issue 1, pp 126–133 | Cite as

The combined effect of MC4R and FTO risk alleles on childhood obesity in Greece

  • Natalia Lazopoulou
  • Eleana Gioka
  • Ioanna Ntalla
  • Panagiota Pervanidou
  • Alexandra-Maria Magiakou
  • Eleftheria Roma-Giannikou
  • George P. Chrousos
  • Ioannis Papassotiriou
  • George Dedoussis
  • Christina Kanaka-Gantenbein
Research paper

Abstract

OBJECTIVE: Single nucleotide polymorphism (SNP) risk alleles of obesogenic genes, such as the fat mass and obesity-associated protein (FTO) and the melanocortin-4 receptor (MC4R) gene, have been described in both paediatrics and adult populations. The aim of this study was to investigate the combined effect of FTO and MC4R risk alleles on the obese phenotype and metabolic profile of young children and adolescents of Greek origin. DESIGN: One hundred and fifty-three overweight and obese Greek children (mean age 11.08±2.23 years) and 151 age-matched normal-weight controls were enrolled. Along with anthropometric and standard biochemical profile genetic analysis for the high-risk rs9939609 A allele of the FTO gene and the high-risk C allele of the rs17782313 polymorphism downstream of the MC4R gene were investigated in all participants. RESULTS: The combined presence of three or more high-risk alleles of both the FTO and MC4R genes confers a 4-fold higher risk for obesity in children and adolescents of Greek origin, although these risk alleles have no impact on the metabolic alterations observed in these obese children and adolescents. CONCLUSIONS: There is a synergistic effect of the high-risk alleles of the FTO and MC4R genes on the obese phenotype, while no impact on the metabolic abnormalities was observed in Greek obese children and adolescents.

Key words

BMI Childhood obesity FTO MC4R Metabolic abnormalities SNP 

References

  1. 1.
    Dietz WH, 1998 Health consequences of obesity in youth: childhood predictors of adult disease. Pediatrics 101: 518–525.PubMedGoogle Scholar
  2. 2.
    Brug J, van Stralen MM, te Velde SJ, et al, 2012 Differences in weight status and energy-balance related behaviors among schoolchildren across Europe: The ENERGY-Project. PLoS ONE 7: e34742.CrossRefGoogle Scholar
  3. 3.
    Chung WK, Leibel RL, 2008 Considerations regarding the genetics of obesity. Obesity (Silver Spring) 16: Suppl 3: 33–39.CrossRefGoogle Scholar
  4. 4.
    Speliotes EK, Willer CJ, Berndt SI, et al, 2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42: 937–948.CrossRefGoogle Scholar
  5. 5.
    Frayling TM, Timpson NJ, Weedon MN, et al, 2007 A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science (New York, NY) 316: 889–894.CrossRefGoogle Scholar
  6. 6.
    Wardle J, Carnell S, Haworth CMA, Farooqi IS, O’Rahilly S, Plomin R, 2008 Obesity associated genetic variation in FTO Is associated with diminished satiety. J Clin Endocrinol Metab 93: 3640–3643.CrossRefGoogle Scholar
  7. 7.
    Tanofsky-Kraff M, Han JC, Anandalingam K, et al, 2009 The FTO gene rs9939609 obesity-risk allele and loss of control over eating. Am J Clin Nutr 90: 1483–1488.CrossRefGoogle Scholar
  8. 8.
    Xi B, Zhang M, Wang C, et al, 2013 The common SNP (rs9939609) in the FTO gene modifies the association between obesity and high blood pressure in Chinese children. Mol Biol Rep 40: 773–778.CrossRefGoogle Scholar
  9. 9.
    Rendo T, Moleres A, Marti Del Moral A, 2009 Effects of the FTO gene on lifestyle intervention studies in children. Obes Facts 2: 393–399.CrossRefGoogle Scholar
  10. 10.
    Vaisse C, Clement K, Guy-Grand B, Froguel P, 1998 A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20: 113–114.CrossRefGoogle Scholar
  11. 11.
    Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P, 2000 Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106: 253–262.CrossRefGoogle Scholar
  12. 12.
    Yeo GS, Lank EJ, Farooqi IS, Keogh J, Challis BG, O’Rahilly S, 2003 Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 12: 561–574.CrossRefGoogle Scholar
  13. 13.
    Lubrano-Berthelier C, Cavazos M, Le Stunff C, et al, 2003 The human MC4R promoter: characterization and role in obesity. Diabetes 52: 2996–3000.CrossRefGoogle Scholar
  14. 14.
    Lubrano-Berthelier C, Durand E, Dubern B, et al, 2003 Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 12: 145–153.CrossRefGoogle Scholar
  15. 15.
    Nijenhuis WA, Garner KM, van Rozen RJ, Adan RA, 2003 Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity. J Biol Chem 278: 22939–22945.CrossRefGoogle Scholar
  16. 16.
    Qi L, Kraft P, Hunter DJ, Hu FB, 2008 The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Hum Mol Genet 17: 3502–3508.CrossRefGoogle Scholar
  17. 17.
    Loos RJF, Lindgren CM, Li S, et al, 2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40: 768–775.CrossRefGoogle Scholar
  18. 18.
    Cauchi S, Stutzmann F, Cavalcanti-Proença C, et al, 2009 Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. J Mol Med 87: 537–546.CrossRefGoogle Scholar
  19. 19.
    Kring SI, Holst C, Toubro S, et al, 2010 Common variants near MC4R in relation to body fat, body fat distribution, metabolic traits and energy expenditure. Int J Obes (Lond) 34: 182–189.CrossRefGoogle Scholar
  20. 20.
    Liu G, Zhu H, Lagou V, et al, 2010 Common variants near melanocortin 4 receptor are associated with general and visceral adiposity in European- and African-American youth. J Pediatr 156: 598–605e1.CrossRefGoogle Scholar
  21. 21.
    Grant SF, Bradfield JP, Zhang H, et al, 2009 Investigation of the locus near MC4R with childhood obesity in Americans of European and African ancestry. Obesity (Silver Spring) 17: 1461–1465.Google Scholar
  22. 22.
    Hardy R, Wills AK, Wong A, et al, 2010 Life course variations in the associations between FTO and MC4R gene variants and body size. Hum Mol Genet 19: 545–552.CrossRefGoogle Scholar
  23. 23.
    Cole TJ, Bellizzi MC, Flegal KM, Dietz WH, 2000 Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320: 1240–1243.CrossRefGoogle Scholar
  24. 24.
    Papoutsakis C, Vidra NV, Hatzopoulou I, et al, 2007 The gene-diet Attica investigation on childhood obesity (GENDAI): overview of the study design. Clin Chem Lab Med 45: 309–315.CrossRefGoogle Scholar
  25. 25.
    Blomeke B, Sieben S, Spotter D, Landt O, Merk HF, 1999 Identification of N-acetytransferase 2 genotypes by continuous monitoring of fluorogenic hybridization probes. Anal Biochem 275: 93–97.CrossRefGoogle Scholar
  26. 26.
    Purcell S, Neale B, Todd-Brown K, et al, 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.CrossRefGoogle Scholar
  27. 27.
    Elks CE, Loos RJF, Hardy R, et al, 2012 Adult obesity susceptibility variants are associated with greater childhood weight gain and a faster tempo of growth: the 1946 British Birth Cohort Study123. Am J Clin Nutr 95: 1150–1156.CrossRefGoogle Scholar
  28. 28.
    Graff M, North KE, Mohlke KL, et al, 2012 Estimation of genetic effects on BMI during adolescence in an ethnically diverse cohort: The National Longitudinal Study of Adolescent Health. Nutr Diabetes 2: e47.CrossRefGoogle Scholar
  29. 29.
    Xi B, Zhang M, Wang C, et al, 2013 The common SNP (rs9939609) in the FTO gene modifies the association between obesity and high blood pressure in Chinese children. Mol Biol Rep 40: 773–778.CrossRefGoogle Scholar
  30. 30.
    Wu L, Xi B, Zhang M, et al, 2010 Associations of six single nucleotide polymorphisms in obesity-related genes with BMI and risk of obesity in Chinese children. Diabetes 59: 3085–3089.CrossRefGoogle Scholar
  31. 31.
    Xi B, Chandak GR, Shen Y, Wang Q, Zhou D, 2012 Association between common polymorphism near the MC4R gene and obesity risk: a systematic review and meta-analysis. PLoS ONE 7: e45731.CrossRefGoogle Scholar
  32. 32.
    Sovio U, Mook-Kanamori DO, Warrington NM, et al, 2011 Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development. PLoS Genet 7: e1001307–e07.CrossRefGoogle Scholar
  33. 33.
    Haworth CM, Carnell S, Meaburn EL, Davis OS, Plomin R, Wardle J, 2008 Increasing heritability of BMI and stronger associations with the FTO gene over childhood. Obesity 16: 2663–2668.CrossRefGoogle Scholar
  34. 34.
    Stovitz SD, Demerath EW, Hannan PJ, Lytle LA, Himes JH, 2011 Growing into obesity: patterns of height growth in those who become normal weight, overweight, or obese as young adults. Am J Hum Biol 23: 635–641.CrossRefGoogle Scholar
  35. 35.
    Andersson EA, Pilgaard K, Pisinger C, et al, 2010 Do gene variants influencing adult adiposity affect birth weight? a population-based study of 24 loci in 4,744 Danish individuals. PLoS ONE 5: e14190.CrossRefGoogle Scholar
  36. 36.
    López-Bermejo A, Petry CJ, Díaz M, et al, 2008 The association between the FTO gene and fat mass in humans develops by the postnatal age of two weeks. J Clin Endocrinol Metab 93: 1501–1505.CrossRefGoogle Scholar
  37. 37.
    Elks CE, Loos RJF, Sharp SJ, et al, 2010 Genetic markers of adult obesity risk are associated with greater early infancy weight gain and growth. PLoS Med 7: e1000284.CrossRefGoogle Scholar
  38. 38.
    Daniels SR, 2011 Lipid concentrations in children and adolescents: it is not all about obesity. Am J Clin Nutr 94: 699–700.CrossRefGoogle Scholar
  39. 39.
    O’Rahilly S, Farooqi IS, 2008 Human obesity: a heritable neurobehavioral disorder that is highly sensitive to environmental conditions. Diabetes 57: 2905–2910.CrossRefGoogle Scholar
  40. 40.
    Xi B, Wang C, Wu L, et al, 2011 Influence of physical inactivity on associations between single nucleotide polymorphisms and genetic predisposition to childhood obesity. Am J Epidemiol 173: 1256–1262.CrossRefGoogle Scholar
  41. 41.
    Vimaleswaran KS, Li S, Zhao JH, et al, 2009 Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene. Am J Clin Nutr 90: 425–428.CrossRefGoogle Scholar
  42. 42.
    Ortega-Azorín C, Sorlí JV, Asensio EM, et al, 2012 Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low. Cardiovasc Diabetol 11: 137.CrossRefGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2015

Authors and Affiliations

  • Natalia Lazopoulou
    • 1
  • Eleana Gioka
    • 1
  • Ioanna Ntalla
    • 2
  • Panagiota Pervanidou
    • 1
  • Alexandra-Maria Magiakou
    • 1
  • Eleftheria Roma-Giannikou
    • 1
  • George P. Chrousos
    • 1
  • Ioannis Papassotiriou
    • 3
  • George Dedoussis
    • 2
  • Christina Kanaka-Gantenbein
    • 1
  1. 1.First Department of PaediatricsUniversity of Athens Medical School, “Aghia Sophia” Children’s HospitalGoudi, AthensGreece
  2. 2.Harokopio University of DieteticsAthensGreece
  3. 3.Department of Clinical Biochemistry“Aghia Sophia” Children’s HospitalAthensGreece

Personalised recommendations