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genome wide association dual-energy x-ray absorptiometry month download article/chapter norwegian population-based cohort professor leena peltonen-palotie case–control studies anna-liisa hartikainen �fondation de france” mc4r genetic variants full article pdf privacy choices/manage cookies molecular medicine aims philippe froguel cross-regional institute obesity-related traits french epidemiological study genetic variants common variation melanocortin-4 receptor results melanocortin-4 receptor deficiency european economic area european general populations obesity related phenotypes body fat accumulation common polymorphisms 3-fold increased susceptibility 8-fold increased risk tuija tammelin jaana laitinen arturo gonzalez-izquierdo environmental factors remained stender-petersen kl asian indian sikhs proopiomelanocortin gene expression bioelectrical impedance accuracy st-onge mp du cane road electronic supplementary material genetic analysis attributable risk percent large general populations fat mass deposition michel marre common obesity variant conditions privacy policy carrying increasing numbers article cauchi fto variants confer age-dependent penetrance dna bank management

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         headline:Combined effects of MC4R and FTO common genetic variants on obesity in European general populations
         description: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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            Population genetics
            Molecular Medicine
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      headline:Combined effects of MC4R and FTO common genetic variants on obesity in European general populations
      description: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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         SNP
         Population genetics
         Molecular Medicine
         Human Genetics
         Internal Medicine
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      name:Stéphane Cauchi
      affiliation:
            name:Pasteur Institute
            address:
               name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
               type:PostalAddress
            type:Organization
      name:Fanny Stutzmann
      affiliation:
            name:Pasteur Institute
            address:
               name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
               type:PostalAddress
            type:Organization
      name:Christine Cavalcanti-Proença
      affiliation:
            name:Pasteur Institute
            address:
               name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
               type:PostalAddress
            type:Organization
      name:Emmanuelle Durand
      affiliation:
            name:Pasteur Institute
            address:
               name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
               type:PostalAddress
            type:Organization
      name:Anneli Pouta
      affiliation:
            name:University of Oulu
            address:
               name:Public Health Science and General Practice, University of Oulu, Oulu, Finland
               type:PostalAddress
            type:Organization
            name:Imperial College London
            address:
               name:Epidemiology and Public Health, Imperial College London, London, UK
               type:PostalAddress
            type:Organization
      name:Anna-Liisa Hartikainen
      affiliation:
            name:University of Oulu
            address:
               name:Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland
               type:PostalAddress
            type:Organization
      name:Michel Marre
      affiliation:
            name:INSERM U695
            address:
               name:INSERM U695, Paris, France
               type:PostalAddress
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            name:René Diderot–Paris 7 University
            address:
               name:René Diderot–Paris 7 University, Paris, France
               type:PostalAddress
            type:Organization
            name:Bichat Claude Bernard Hospital
            address:
               name:Endocrinology–Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris, France
               type:PostalAddress
            type:Organization
      name:Sylviane Vol
      affiliation:
            name:Regional Institute for Health
            address:
               name:Regional Institute for Health, La Riche, France
               type:PostalAddress
            type:Organization
      name:Tuija Tammelin
      affiliation:
            name:Finnish Institute of Occupational Health
            address:
               name:Finnish Institute of Occupational Health, Helsinki, Finland
               type:PostalAddress
            type:Organization
      name:Jaana Laitinen
      affiliation:
            name:Finnish Institute of Occupational Health
            address:
               name:Finnish Institute of Occupational Health, Helsinki, Finland
               type:PostalAddress
            type:Organization
      name:Arturo Gonzalez-Izquierdo
      affiliation:
            name:Imperial College London
            address:
               name:Epidemiology and Public Health, Imperial College London, London, UK
               type:PostalAddress
            type:Organization
      name:Alexandra IF Blakemore
      affiliation:
            name:Imperial College London
            address:
               name:Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
               type:PostalAddress
            type:Organization
      name:Paul Elliott
      affiliation:
            name:Imperial College London
            address:
               name:Epidemiology and Public Health, Imperial College London, London, UK
               type:PostalAddress
            type:Organization
      name:David Meyre
      affiliation:
            name:Pasteur Institute
            address:
               name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
               type:PostalAddress
            type:Organization
      name:Beverley Balkau
      affiliation:
            name:INSERM U780–IFR69
            address:
               name:INSERM U780–IFR69, Villejuif, France
               type:PostalAddress
            type:Organization
            name:University of Paris-Sud
            address:
               name:University of Paris-Sud, Paris, France
               type:PostalAddress
            type:Organization
      name:Marjo-Riitta Järvelin
      affiliation:
            name:Imperial College London
            address:
               name:Epidemiology and Public Health, Imperial College London, London, UK
               type:PostalAddress
            type:Organization
            name:University of Oulu
            address:
               name:Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland
               type:PostalAddress
            type:Organization
            name:National Public Health Institute
            address:
               name:Department of Child and Adolescent Health, National Public Health Institute, Helsinki, Finland
               type:PostalAddress
            type:Organization
      name:Philippe Froguel
      affiliation:
            name:Pasteur Institute
            address:
               name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
               type:PostalAddress
            type:Organization
            name:Imperial College London
            address:
               name:Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
      name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
      name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
      name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
      name:Public Health Science and General Practice, University of Oulu, Oulu, Finland
      name:Epidemiology and Public Health, Imperial College London, London, UK
      name:Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland
      name:INSERM U695, Paris, France
      name:René Diderot–Paris 7 University, Paris, France
      name:Endocrinology–Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris, France
      name:Regional Institute for Health, La Riche, France
      name:Finnish Institute of Occupational Health, Helsinki, Finland
      name:Finnish Institute of Occupational Health, Helsinki, Finland
      name:Epidemiology and Public Health, Imperial College London, London, UK
      name:Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
      name:Epidemiology and Public Health, Imperial College London, London, UK
      name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
      name:INSERM U780–IFR69, Villejuif, France
      name:University of Paris-Sud, Paris, France
      name:Epidemiology and Public Health, Imperial College London, London, UK
      name:Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland
      name:Department of Child and Adolescent Health, National Public Health Institute, Helsinki, Finland
      name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
      name:Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
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