Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children

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Tuomas O. Kilpeläinen¹, Lu Qi²^*, Soren Brage¹, Stephen J. Sharp¹, Emily Sonestedt³, Ellen Demerath⁴, Tariq Ahmad⁵, Samia Mora⁶, Marika Kaakinen⁷, Camilla Helene Sandholt⁸, Christina Holzapfel⁹^,¹⁰, Christine S. Autenrieth¹¹, Elina Hyppönen¹², Stéphane Cauchi¹³, Meian He¹⁴, Zoltan Kutalik¹⁵, Meena Kumari¹⁶, Alena Stančáková¹⁷, Karina Meidtner¹⁸, Beverley Balkau¹⁹^,²⁰, Jonathan T. Tan²¹, Massimo Mangino²², Nicholas J. Timpson²³, Yiqing Song²⁴, M. Carola Zillikens²⁵^,²⁶, Kathleen A. Jablonski²⁷, Melissa E. Garcia²⁸, Stefan Johansson²⁹^,³⁰, Jennifer L. Bragg-Gresham³¹, Ying Wu³², Jana V. van Vliet-Ostaptchouk³³, N. Charlotte Onland-Moret³⁴^,³⁵, Esther Zimmermann³⁶^,³⁷, Natalia V. Rivera³⁸, Toshiko Tanaka³⁹^,⁴⁰, Heather M. Stringham³¹, Günther Silbernagel⁴¹, Stavroula Kanoni⁴², Mary F. Feitosa⁴³, Soren Snitker⁴⁴, Jonatan R. Ruiz⁴⁵^,⁴⁶, Jeffery Metter⁴⁰, Maria Teresa Martinez Larrad⁴⁷, Mustafa Atalay⁴⁸, Maarit Hakanen⁴⁹, Najaf Amin³⁸, Christine Cavalcanti-Proença¹³, Anders Grøntved⁵⁰, Göran Hallmans⁵¹, John-Olov Jansson⁵², Johanna Kuusisto¹⁷, Mika Kähönen⁵³, Pamela L. Lutsey⁴, John J. Nolan⁵⁴, Luigi Palla¹, Oluf Pedersen⁸^,³⁷^,⁵⁵^,⁵⁶, Louis Pérusse⁵⁷, Frida Renström²^,³^,⁵⁸, Robert A. Scott¹, Dmitry Shungin³^,⁵⁸^,⁵⁹, Ulla Sovio⁶⁰, Tuija H. Tammelin⁶¹^,⁶², Tapani Rönnemaa⁶³, Timo A. Lakka⁴⁸, Matti Uusitupa⁶⁴^,⁶⁵, Manuel Serrano Rios⁴⁷, Luigi Ferrucci⁴⁰, Claude Bouchard⁶⁶, Aline Meirhaeghe⁶⁷, Mao Fu⁶⁸, Mark Walker⁶⁹, Ingrid B. Borecki⁴³, George V. Dedoussis⁴², Andreas Fritsche⁴¹, Claes Ohlsson⁷⁰, Michael Boehnke³¹, Stefania Bandinelli⁷¹, Cornelia M. van Duijn²⁶^,³⁸^,⁷², Shah Ebrahim⁷³, Debbie A. Lawlor²³, Vilmundur Gudnason⁷⁴^,⁷⁵, Tamara B. Harris⁷⁶, Thorkild I. A. Sørensen³⁶, Karen L. Mohlke³², Albert Hofman²⁶^,³⁸, André G. Uitterlinden²⁵^,²⁶^,³⁸, Jaakko Tuomilehto⁷⁷^,⁷⁸^,⁷⁹, Terho Lehtimäki⁸⁰, Olli Raitakari⁴⁹^,⁸¹, Bo Isomaa⁸²^,⁸³, Pål R. Njølstad³⁰^,, Jose C. Florez⁸⁵^,⁸⁶^,⁸⁷, Simin Liu⁸⁸, Andy Ness⁸⁹, Timothy D. Spector²², E. Shyong Tai⁹⁰, Philippe Froguel¹³^,⁹¹, Heiner Boeing¹⁸, Markku Laakso¹⁷, Michael Marmot⁹², Sven Bergmann¹⁵, Chris Power¹², Kay-Tee Khaw⁹³, Daniel Chasman⁶, Paul Ridker⁶, Torben Hansen⁸^,⁵⁶^,⁹⁴, Keri L. Monda⁹⁵, Thomas Illig⁹, Marjo-Riitta Järvelin⁷^,⁹⁶^,⁹⁷, Nicholas J. Wareham¹, Frank B. Hu¹⁴, Leif C. Groop³, Marju Orho-Melander³, Ulf Ekelund¹, Paul W. Franks²^,³^,⁵⁸^*, Ruth J. F. Loos¹^*

1 Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, United Kingdom, 2 Departments of Epidemiology and Nutrition, Harvard University School of Public Health, Boston, Massachusetts, United States of America, 3 Lund University Diabetes Centre, Department of Clinical Sciences, Skane University Hospital, Lund University, Malmo, Sweden, 4 Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America, 5 Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America, 6 Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 7 Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland, 8 Hagedorn Research Institute, Gentofte, Denmark, 9 Unit for Molecular Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany, 10 Else Kroener-Fresenius-Centre for Nutritional Medicine, Technische Universität München, University Hospital “Klinikum rechts der Isar,” Munich, Germany, 11 Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany, 12 Centre for Paediatric Epidemiology and Biostatistics and Medical Research Council Centre of Epidemiology for Child Health, University College London Institute of Child Health, London, United Kingdom, 13 CNRS-UMR-8090, Department of Genomics and Molecular Physiology of Metabolic Diseases, Institute of Biology of Lille, Lille, France, 14 Harvard School of Public Health, Boston, Massachusetts, United States of America, 15 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland, 16 Genetic Epidemiology Group, Department of Epidemiology, University College London, London, United Kingdom, 17 Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, 18 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany, 19 INSERM, CESP Centre for Research in Epidemiology and Population Health, U1018, Epidemiology of diabetes, obesity and chronic kidney disease over the lifecourse and determinants of early nutrition, Villejuif, France, 20 University Paris Sud 11, UMRS 1018, Villejuif, France, 21 Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 22 King’s College London, London, United Kingdom, 23 Medical Research Council Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom, 24 Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 25 Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands, 26 Netherlands Genomics Initiative–sponsored Netherlands Consortium for Healthy Aging, Leiden, The Netherlands, 27 The Biostatistics Center, George Washington University, Rockville, Maryland, United States of America, 28 National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America, 29 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway, 30 Department of Clinical Medicine, University of Bergen, Bergen, Norway, 31 Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America, 32 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America, 33 Molecular Genetics Section, Department of Pathology and Medical Biology, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands, 34 Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands, 35 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands, 36 Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark, 37 Institute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, 38 Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands, 39 Medstar Research Institute, Baltimore, Maryland, United States of America, 40 Longitudinal Study Section, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America, 41 Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany, 42 Department of Nutrition-Dietetics, Harokopio University of Athens, Athens, Greece, 43 Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, United States of America, 44 University of Maryland School of Medicine, College Park, Maryland, United States of America, 45 Unit for Preventive Nutrition, Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, Huddinge, Sweden, 46 Department of Physical Education and Sport, School of Physical Activity and Sport Sciences, University of Granada, Granada, Spain, 47 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Hospital Clínico San Carlos, Madrid, Spain, 48 Institute of Biomedicine, Department of Physiology, University of Eastern Finland, Kuopio Campus, Kuopio, Finland, 49 The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland, 50 Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark, 51 Department of Public Health and Clinical Medicine Section for Nutritional Research, Umeå University, Umeå, Sweden, 52 Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, 53 Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland, 54 Steno Diabetes Centre, Gentofte, Denmark, 55 Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark, 56 Marie Krogh Center for Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, 57 Division of Kinesiology, Department of Social and Preventive Medicine, Laval University, Ste-Foy, Quebec, Canada, 58 Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden, 59 Department of Odontology, Umeå University, Umeå, Sweden, 60 Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom, 61 Finnish Institute of Occupational Health, Oulu, Finland, 62 LIKES Research Center for Sport and Health Sciences, Jyväskylä, Finland, 63 Department of Medicine, University of Turku, Turku, Finland, 64 Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, Finland, 65 Research Unit, Kuopio University Hospital, Kuopio, Finland, 66 Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States of America, 67 INSERM, U744, Institut Pasteur de Lille, Université Lille Nord de France, Université Lille 2, Lille, France, 68 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, United States of America, 69 Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle, United Kingdom, 70 Centre for Bone and Arthritis Research, Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, 71 Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Florence, Italy, 72 Netherlands Genomics Initiative, Centre for Medical Systems Biology, Leiden, The Netherlands, 73 Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom, 74 Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Kopavogur, Iceland, 75 University of Iceland, Reykjavik, Iceland, 76 Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America, 77 Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland, 78 South Ostrobothnia Central Hospital, Seinäjoki, Finland, 79 Department of Clinical and Preventive Medicine, Danube-University Krems, Krems, Austria, 80 Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland, 81 Department of Clinical Physiology, Turku University Hospital, Turku, Finland, 82 Folkhälsan Research Centre, Helsinki, Finland, 83 Department of Social Services and Health Care, Jakobstad, Finland, Department of Pediatrics, Haukeland University Hospital, Bergen, Norway, 85 Center for Human Genetic Research and Diabetes Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 86 Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America, 87 Program for Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America, 88 Center for Metabolic Disease Prevention, School of Public Health and David Geffen School of Medicine, University of California, Los Angeles, California, United States of America, 89 School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom, 90 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 91 Centre and Department of Genomic Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom, 92 Department of Epidemiology and Public Health, University College London, London, United Kingdom, 93 Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom, 94 Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark, 95 Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America, 96 Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom, 97 Department of Life Course and Services, National Institute for Health and Welfare, Oulu, Finland

Abstract Top

Background

The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).

Methods and Findings

All studies identified to have data on the FTO rs9939609 variant (or any proxy [r²>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A−) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20–1.26), but PA attenuated this effect (p_interaction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19–1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24–1.36). No such interaction was found in children and adolescents.

Conclusions

The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

Please see later in the article for the Editors' Summary

Citation: Kilpeläinen TO, Qi L, Brage S, Sharp SJ, Sonestedt E, et al. (2011) Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children. PLoS Med 8(11): e1001116. doi:10.1371/journal.pmed.1001116

Academic Editor: Cathryn Lewis, Kings College London, United Kingdom

Received: April 21, 2011; Accepted: September 23, 2011; Published: November 1, 2011

Copyright: © 2011 Loos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: There was no specific funding for this project/meta-analysis. Funding sources for the individual authors and for the studies included in the meta-analysis are listed in Text S2. The publication is the work of the authors, and the views in this paper are not necessarily those of any funding body. No funding body has dictated how analyses were undertaken or results interpreted, and Ruth Loos acts as guarantor for the contents.

Competing interests: JJN has, since January 2011, been employed at Steno Diabetes Centre, a legally independent clinical and research body, which is wholly owned by Novo Nordisk. In relation to his contribution to this manuscript (through the RISC study), all of this work pre-dates his appointment to his current position. All other authors have declared that no competing interests exist.

Abbreviations: BMI, body mass index; OR, odds ratio; PA, physical activity; SNP, single nucleotide polymorphism

* E-mail: luqi@hsph.harvard.edu (LQ); paul.franks@med.lu.se (PWF); ruth.loos@mrc-epid.cam.ac.uk (RJFL)

full-text:
PLoS Medicine: Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children