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Research Article

Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits

  • Angelo Scuteri equal contributor,

    equal contributor Contributed equally to this work with: Angelo Scuteri, Serena Sanna

    Affiliations: Unità Operativa Geriatria, Istituto per la Patologia Endocrina e Metabolica, Rome, Italy, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America

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  • Serena Sanna equal contributor,

    equal contributor Contributed equally to this work with: Angelo Scuteri, Serena Sanna

    Affiliations: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America, Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Wei-Min Chen,

    Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America

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  • Manuela Uda,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Giuseppe Albai,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • James Strait,

    Affiliation: Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America

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  • Samer Najjar,

    Affiliation: Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America

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  • Ramaiah Nagaraja,

    Affiliation: Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America

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  • Marco Orrú,

    Affiliations: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy, Unità Operativa Semplice Cardiologia, Divisione di Medicina, Presidio Ospedaliero Santa Barbara, Iglesias, Italy

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  • Gianluca Usala,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Mariano Dei,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Sandra Lai,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Andrea Maschio,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Fabio Busonero,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Antonella Mulas,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Georg B Ehret,

    Affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America

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  • Ashley A Fink,

    Affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America

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  • Alan B Weder,

    Affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America

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  • Richard S Cooper,

    Affiliation: Department of Preventive Medicine and Epidemiology, Loyola Stritch School of Medicine, Chicago, Illinois, United States of America

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  • Pilar Galan,

    Affiliations: Institut Scientifique et Technique de la Nutrition et de l'Alimentation, Paris, France, INSERM, U557 (UMR INSERM/INRA/CNAM), Paris, France

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  • Aravinda Chakravarti,

    Affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America

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  • David Schlessinger mail,

    To whom correspondence should be addressed. E-mail: schlessingerd@grc.nia.nih.gov (DS); goncalo@umich.edu (GRA)

    Affiliation: Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America

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  • Antonio Cao,

    Affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

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  • Edward Lakatta,

    Affiliation: Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America

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  • Gonçalo R Abecasis mail

    To whom correspondence should be addressed. E-mail: schlessingerd@grc.nia.nih.gov (DS); goncalo@umich.edu (GRA)

    Affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America

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  • Published: July 20, 2007
  • DOI: 10.1371/journal.pgen.0030115

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Significant Relationships Between FTO Variants and 5-Year BMI Changes in Children and Adolescents of the Stanislas Cohort

Posted by PLoS_Genetics on 26 Feb 2008 at 13:58 GMT

Originally submitted as a Reader Response by Sophie Visvikis-Siest (sophie.visvikis-siest@nancy.inserm.fr) on 14 February 2008 (additional authors: Anastasia Samara, David Meyre, Bernard Herbeth, Philippe Froguel):

Recent studies have shown significant associations of SNPs in the FTO gene, with increased BMI and obesity in childhood and adult life [1,2], as well as with obesity traits (BMI, hip circumference and weight) [3]. Some SNPs were enhanced: rs9939609, rs9930506, rs17817449, and rs1421085 are all strongly associated within them, in high linkage disequilibrium. The above cited investigations, all based on cross-sectional studies, are the only existing ones providing some evidence on relationships between FTO and the prevalence of obesity. However, no longitudinal study provides further information on relationships between these gene polymorphisms and short-term weight gain and potential age-related differences.

Therefore, in a sub-sample of the STANISLAS cohort, including middle-aged adults (391 subjects aged 30 to 54 years) and children and adolescents (430 subjects aged 5 to 20 years), without extreme obesity, we tested the association of two SNPs: rs1421085 and rs17817449 (allelic frequency 0.421 and 0.412 respectively) with 5-year BMI changes. Variability of BMI with age and sex was controlled by using BMI Z-scores in analysis and FTO polymorphisms were determined by using the Applied Biosystems SNPlexTM Technology [1].

In children and adolescents, after adjustment for age, sex and BMI Z-score at entrance, means for five-year change in BMI Z-score were significantly higher in carriers of the “G” allele at rs17817449 (p for the additive model = 0.049) and in carriers of the “C” allele at rs1421085 (p for the additive model = 0.033). Means: the SEM (standard error of mean) were -0.049–0.054, 0.027–0.041 and 0.126–0.072, for TT, GT and GG genotype classes, respectively, and the estimated additive effect was 0.085 per allele [Generalized Estimating Equation (GEE) procedure] for rs17817449 and -0.050–0.055, 0.020–0.042 and 0.134–0.063, for TT, CT, and CC genotype classes, respectively, and the estimated additive effect was 0.088 per allele, for rs1421085. In adults, associations of these two polymorphisms with five-year change in BMI Z-score were not statistically significant (p=0.823 and 0.538, respectively).

In the present study, the alleles associated with increase in BMI are the same as those described by Dina et al [1] of the chosen SNPs. Scuteri et al [3] have shown associations for the rs9930506 FTO variant with BMI, in a prospective way and Fraying et al [2], in a cross-sectional study, estimated an increased risk for developing obesity in children and adult carriers of the rs9939609 FTO SNP. Our study provides new evidence on the relationships of FTO variants with evolution of BMI over time. The effect of the two FTO variants in subjects not suffering from severe or morbid obesity suggests an implication of this gene in physiological mechanisms regulating BMI.

As for the significant relationships we found in children/adolescents, some explanations could be given. FTO is eventually implicated in different physiological functions in puberty that do not persist in adult life, suggesting that the impact of FTO on BMI depends on age. Additionally, the environmental background is modified with age and that may mask an eventual effect of genetic parameters as those of FTO. Moreover, we must take into consideration the size of our population, which could probably explain the absence of relationships in the adult population.


References
1. Dina C, Meyre D, Gallina S, Durand E, Korner A et al. (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39: 724-726.
2. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM et al. (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316: 889-894.
3. Scuteri A, Sanna S, Chen WM, Uda M, Albai G et al. (2007) Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits. PLoS Genet 3: e115.