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Combined effects of MC4R and FTO common genetic variants on obesity in European general populations

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Abstract

Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20–24% of the populations), subjects with three or four risk alleles (7–10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (~1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm3 (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.

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Acknowledgements

This work was partly supported by the French Government “Agence Nationale de la Recherche”, and the charities: “Association Française des Diabétiques” and “Programme national de recherche sur le diabète”. We thank Marianne Deweider and Frederic Allegaert for the DNA bank management. We are indebted to all subjects who participated to this study. The D.E.S.I.R. study has been supported by CNAMTS, Lilly, Novartis Pharma, and Sanofi-Aventis, by INSERM (“Réseaux en Santé Publique, Interactions entre les déterminants de la santé”), by “Association Diabète Risque Vasculaire”, “Fédération Française de Cardiologie”, “Fondation de France”, ALFEDIAM, ONIVINS, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, and Topcon. The D.E.S.I.R. Study Group: INSERM U780: B. Balkau, P. Ducimetière, E. Eschwège; INSERM U367: F. Alhenc-Gelas; CHU D'Angers: Y. Gallois, A. Girault; Bichat Hospital: F. Fumeron, M. Marre; Medical Examination Services: Alençon, Angers, Caen, Chateauroux, Cholet, Le Mans, and Tours; Research Institute for General Medicine: J. Cogneau; General practitioners of the region; Cross-Regional Institute for Health: C. Born, E. Caces, M. Cailleau, J. G. Moreau, F. Rakotozafy, J. Tichet, S. Vol. The NFBC 1986 study has been supported by the Oulu University Hospital, Finland, the Academy of Finland, and the European Commission (Framework 5 award QLG1-CT-2000-01643). We thank Professor Leena Peltonen-Palotie for her contribution in DNA extraction and distribution.

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Authors and Affiliations

  1. CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France

    Stéphane Cauchi, Fanny Stutzmann, Christine Cavalcanti-Proença, Emmanuelle Durand, David Meyre & Philippe Froguel

  2. Public Health Science and General Practice, University of Oulu, Oulu, Finland

    Anneli Pouta

  3. Epidemiology and Public Health, Imperial College London, London, UK

    Anneli Pouta, Arturo Gonzalez-Izquierdo, Paul Elliott & Marjo-Riitta Järvelin

  4. Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland

    Anna-Liisa Hartikainen

  5. INSERM U695, Paris, France

    Michel Marre

  6. René Diderot–Paris 7 University, Paris, France

    Michel Marre

  7. Endocrinology–Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris, France

    Michel Marre

  8. Regional Institute for Health, La Riche, France

    Sylviane Vol

  9. Finnish Institute of Occupational Health, Helsinki, Finland

    Tuija Tammelin & Jaana Laitinen

  10. Genomic Medicine, Hammersmith Hospital, Imperial College London, Du Cane Road, London, W12 0NN, UK

    Alexandra IF Blakemore & Philippe Froguel

  11. INSERM U780–IFR69, Villejuif, France

    Beverley Balkau

  12. University of Paris-Sud, Paris, France

    Beverley Balkau

  13. Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland

    Marjo-Riitta Järvelin

  14. Department of Child and Adolescent Health, National Public Health Institute, Helsinki, Finland

    Marjo-Riitta Järvelin

Authors
  1. Stéphane Cauchi
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  2. Fanny Stutzmann
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  3. Christine Cavalcanti-Proença
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  4. Emmanuelle Durand
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  7. Michel Marre
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  8. Sylviane Vol
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  10. Jaana Laitinen
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  11. Arturo Gonzalez-Izquierdo
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  12. Alexandra IF Blakemore
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  13. Paul Elliott
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  14. David Meyre
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  15. Beverley Balkau
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  16. Marjo-Riitta Järvelin
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  17. Philippe Froguel
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Corresponding author

Correspondence to Philippe Froguel.

Additional information

Marjo-Riitta Järvelin and Philippe Froguel equally contributed to this work.

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Table S1

Effects of FTO and MC4R genetic variants on fat mass during adulthood (DOC 34 KB).

Table S2

Subjects excluded from analysis (DOC 45.5 KB).

Fig. S1

Interaction of FTO with physical activity on Z-BMI in adolescents (NFBC 1986, a) and on obesity in middle-aged adults (D.E.S.I.R., b). Physical activity: adults [1–4 = hours of physical activity per week], adolescents [1 = inactive (less than 1 h a week); 2 = somewhat active (1–3 h a week); 3 = active (four or more hours per week)] (DOC 103 KB).

Fig. S2

Effects on T2D in middle-aged adults (D.E.S.I.R.) carrying increasing numbers of FTO and MC4R risk alleles (DOC 25.5 KB).

Fig. S3

Interaction of MC4R with gender on obesity (a) and fat mass (b) in adults (D.E.S.I.R.) (DOC 28.5 KB).

Fig. S4

Effects on fat mass in adults (D.E.S.I.R.) carrying increasing numbers of FTO and MC4R risk alleles (DOC 26 KB).

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Cauchi, S., Stutzmann, F., Cavalcanti-Proença, C. et al. Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. J Mol Med 87, 537–546 (2009). https://doi.org/10.1007/s00109-009-0451-6

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  • DOI: https://doi.org/10.1007/s00109-009-0451-6

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