1. On the Futility of Screening for Genes That Make You Fat
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Terho Lehtimäki, Emily Sonestedt, Göran Hallmans, Andy R Ness, Simin Liu, Tuija Tammelin, John J. Nolan, Massimo Mangino, Nicholas J. Timpson, George Dedoussis, Aline Meirhaeghe, Lu Qi, Pål R. Njølstad, Ruth J. F. Loos, Mustafa Atalay, Mao Fu, Natalia V. Rivera, Marju Orho-Melander, Thorkild I. A. Sørensen, Philippe Froguel, André G. Uitterlinden, Torben Hansen, Debbie A Lawlor, M. Carola Zillikens, Tapani Rönnemaa, Vilmundur Gudnason, Esther Zimmermann, Claes Ohlsson, Cornelia M. van Duijn, Paul M. Ridker, Marjo-Riitta Järvelin, Samia Mora, María Teresa Martínez Larrad, Alena Stančáková, Thomas Illig, Zoltán Kutalik, Sven Bergmann, Jonatan R. Ruiz, Luigi Palla, Kathleen A. Jablonski, Günther Silbernagel, Ulla Sovio, Soren Snitker, Karina Meidtner, Bo Isomaa, Stephen J. Sharp, Jana V. van Vliet-Ostaptchouk, Louis Pérusse, Mika Kähönen, Daniel I. Chasman, Najaf Amin, Johanna Kuusisto, Toshiko Tanaka, Ingrid B. Borecki, John-Olov Jansson, Christine Cavalcanti-Proença, N. Charlotte Onland-Moret, Kay-Tee Khaw, Camilla H. Sandholt, Ulf Ekelund, Luigi Ferrucci, Mark Walker, Yiqing Song, Jose C. Florez, Oluf Pedersen, Leif Groop, Ying Wu, Soren Brage, Tuomas O. Kilpeläinen, Anders Grøntved, Frida Renström, Meena Kumari, Stéphane Cauchi, Michael Boehnke, Tamara B. Harris, Christine S. Autenrieth, Jeffery Metter, Beverley Balkau, Dmitry Shungin, Karen L. Mohlke, Markku Laakso, Matti Uusitupa, Nicholas J. Wareham, Andreas Fritsche, Jaakko Tuomilehto, Albert Hofman, Shah Ebrahim, Mary F. Feitosa, Melissa E. Garcia, Stefan Johansson, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Frank B. Hu, Jonathan T. Tan, Maarit Hakanen, Heiner Boeing, Manuel Serrano Ríos, Olli T. Raitakari, Michael Marmot, Meian He, Jennifer L. Bragg-Gresham, Claude Bouchard, Tariq Ahmad, Ellen W. Demerath, Keri L. Monda, Robert A. Scott, Marika Kaakinen, Chris Power, Stefania Bandinelli, Christina Holzapfel, Timo A. Lakka, Heather M. Stringham, Stavroula Kanoni, Elina Hyppönen, Pamela L. Lutsey, Internal Medicine, Medical Microbiology & Infectious Diseases, Epidemiology, Urology, Institute of Metabolic Science, MRC, Departments of Epidemiology and Nutrition, Harvard School of Public Health, Department of Clinical Sciences, Lund University Diabetes Centre-Lund University [Lund], Division of Epidemiology and Community Health, University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Division of Cardiology, Duke University Medical Center, Brigham and Women's Hospital [Boston], Institute of Health Sciences and Biocenter Oulu, University of Oulu, Hagedorn Research Institute, Else Kroener Fresenius Centre - Zentralinstitut für Ernährungs und Lebensmittelfors (ZIEL), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Department of Population Health Sciences, University of Wisconsin-Madison, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Genetics, Université de Lausanne (UNIL), Department of Epidemiology and Public Health, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Department of Epidemiology, Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association-Leibniz Association, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National University of Singapore (NUS)-Yong Loo Lin School of Medicine, King‘s College London, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, Division of Preventive Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), The Biostatistics Center, The George Washington University (GW), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Mental Health Sciences Unit, Department of Clinical Medicine, University of Bergen (UiB), Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Genetics, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Complex Genetics Section, University Medical Center [Utrecht], Julius Center for Health Sciences and Primary Care, Institute of Preventive Medicine, Copenhagen University Hospital, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Genetic Epidemiology Unit, Medstar Research Institute, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Department of Nutrition-Dietetics, Harokopio University of Athens, Division of Statistical Genomics, Washington University School of Medicine, University of Maryland School of Medicine, University of Maryland System, Unit for Preventive Nutrition, Karolinska Institutet [Stockholm], Department of Physical Education and Sport, University of Granada [Granada], Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Hospital Clínico San Carlos, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark (SDU), Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU)-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Clinical Physiology, University of Tampere [Finland]-Tampere University Hospital, Steno Diabetes Centre, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health Sciences, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Odontology, Department of Medical Statistics, London School of Hygiene and Tropical Medicine (LSHTM), LIKES Research Center for Sport and Health Sciences, Finnish Institute of Occupational Health, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana State University (LSU)-Louisiana State University (LSU), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Division of Endocrinology, Diabetes and Nutrition, University of Maryland System-University of Maryland System, Institute of Cell and Molecular Biosciences, Newcastle University [Newcastle], Centre for Bone and Arthritis Research, Institute of Medicine-University of Gothenburg (GU), Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Centre for Medical Systems Biology, Faculty of Epidemiology and Population Health [London], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Department of Clinical Chemistry, Turku University Hospital (TYKS), Folkhälsan Research Centre, Department of Pediatrics, Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB), Center for Human Genetic Research and Diabetes Research Center, Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Program for Medical and Population Genetics, Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Center for Metabolic Disease Prevention, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, School of Oral and Dental Sciences, University of Bristol [Bristol], National University of Singapore (NUS), Department of Genomics of Common Disease, Imperial College London, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Department of Epidemiology and Biostatistics, Department of Life Course and Services, National Institute for Health and Welfare [Helsinki], Autard, Delphine, Lund University [Lund], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Universidad de Granada = University of Granada (UGR), University of Gothenburg (GU)-Institute of Medicine, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), Medical Research Council (MRC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Brage, Soren [0000-0002-1265-7355], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Khaw, Kay-Tee [0000-0002-8802-2903], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Hjelt Institute (-2014), Harvard University-Massachusetts Institute of Technology (MIT)-Harvard University-Massachusetts Institute of Technology (MIT), Kilpeläinen, Tuomas O, Qi, Lu, Brage, Soren, Sharp, Stephen J, Hypponen, Elina, and Loos, Ruth JF
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Male ,Heredity ,endocrine system diseases ,Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714 [VDP] ,Epidemiology ,Social and Behavioral Sciences ,no keywords ,MESH: Genotype ,0302 clinical medicine ,MESH: Child ,GENETIC-VARIANTS ,MESH: Proteins ,10. No inequality ,Child ,0303 health sciences ,Anthropometry ,MESH: Polymorphism, Single Nucleotide ,General Medicine ,11 Medical And Health Sciences ,Genomics ,MESH: Motor Activity ,Adipose Tissue ,Perspective ,Medicine ,Public Health ,WAIST CIRCUMFERENCE ,MESH: Adipose Tissue ,medicine.medical_specialty ,Genotype ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO ,Endocrinology and Diabetes ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Genomic Medicine ,Genetics ,Humans ,Genetic Testing ,Gene Prediction ,Biology ,Adipose Tissue/metabolism ,Adolescent ,Adult ,Aged ,Female ,Genetic Predisposition to Disease ,Motor Activity ,Obesity/genetics ,Obesity/metabolism ,Polymorphism, Single Nucleotide ,Proteins/genetics ,Risk Factors ,MESH: Adolescent ,Science & Technology ,MESH: Humans ,Computational Biology ,nutritional and metabolic diseases ,Proteins ,MESH: Adult ,Odds ratio ,medicine.disease ,Obesity ,RS9939609 POLYMORPHISM ,Endocrinology ,Anthropology ,Physiological Processes ,Body mass index ,MESH: Female ,Population Genetics ,obesity ,Genetic Screens ,Anatomy and Physiology ,FTO gene ,IDENTICAL-TWINS ,MESH: Risk Factors ,MESH: Obesity ,adolescents ,030212 general & internal medicine ,MESH: Aged ,MESH: Genetic Predisposition to Disease ,3142 Public health care science, environmental and occupational health ,ENVIRONMENT INTERACTION ,Genetic Epidemiology ,childhood obesity ,Life Sciences & Biomedicine ,Research Article ,Clinical Research Design ,UNITED-STATES ,WEIGHT-LOSS ,Childhood obesity ,body weight ,Medicine, General & Internal ,Genome Analysis Tools ,Internal medicine ,General & Internal Medicine ,medicine ,Allele ,Sports and Exercise Medicine ,Genetic Association Studies ,030304 developmental biology ,Nutrition ,Clinical Genetics ,Population Biology ,business.industry ,Human Genetics ,MESH: Male ,COMMON VARIANT ,meta-analysis ,Minor allele frequency ,BODY-MASS INDEX ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Genetics of Disease ,Genetic Polymorphism ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Meta-Analyses ,business ,Energy Metabolism ,genetic predisposition ,DIABETES PREVENTION - Abstract
Ruth Loos and colleagues report findings from a meta-analysis of multiple studies examining the extent to which physical activity attenuates effects of a specific gene variant, FTO, on obesity in adults and children. They report a fairly substantial attenuation by physical activity on the effects of this genetic variant on the risk of obesity in adults., 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 [r 2>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, Editors’ Summary Background Two in three Americans are overweight, of whom half are obese, and the trend towards increasing obesity is now seen across developed and developing countries. There has long been interest in understanding the impact of genes and environment when it comes to apportioning responsibility for obesity. Carrying a change in the FTO gene is common (found in three-quarters of Europeans and North Americans) and is associated with a 20%–30% increased risk of obesity. Some overweight or obese individuals may feel that the dice are loaded and there is little point in fighting the fat; it has been reported that those made aware of their genetic susceptibility to obesity may still choose a poor diet. A similar fatalism may occur when overweight and obese people consider physical activity. But disentangling the influence of physical activity on those genetically susceptible to obesity from other factors that might impact weight is not straightforward, as it requires large sample sizes, could be subject to publication bias, and may rely on less than ideal self-reporting methods. Why Was This Study Done? The public health ramifications of understanding the interaction between genetic susceptibility to obesity and physical activity are considerable. Tackling the rising prevalence of obesity will inevitably include interventions principally aimed at changing dietary intake and/or increasing physical activity, but the evidence for these with regards to those genetically susceptible has been lacking to date. The authors of this paper set out to explore the interaction between the commonest genetic susceptibility trait and physical activity using a rigorous meta-analysis of a large number of studies. What Did the Researchers Do and Find? The authors were concerned that a meta-analysis of published studies would be limited both by the data available to them and by possible bias. Instead of this more widely used approach, they took the literature search as their starting point, identified other studies through their collaborators’ network, and then undertook a meta-analysis of all available studies using a new and standardized analysis plan. This entailed an extremely large number of authors mining their data afresh to extract the relevant data points to enable such a meta-analysis. Physical activity was identified in the original studies in many different ways, including by self-report or by using an external measure of activity or heart rate. In order to perform the meta-analysis, participants were labeled as physically active or inactive in each study. For studies that had used a continuous scale, the authors decided that the bottom 20% of the participants were inactive (10% for children and adolescents). Using data from over 218,000 adults, the authors found that carrying a copy of the susceptibility gene increased the odds of obesity by 1.23-fold. But the size of this influence was 27% less in the genetically susceptible adults who were physically active (1.22-fold) compared to those who were physically inactive (1.30-fold). In a smaller study of about 19,000 children, no such effect of physical activity was seen. What Do these Findings Mean? This study demonstrates that people who carry the susceptibility gene for obesity can benefit from physical activity. This should inform health care professionals and the wider public that the view of genetically determined obesity not being amenable to exercise is incorrect and should be challenged. Dissemination, implementation, and ensuring uptake of effective physical activity programs remains a challenge and deserves further consideration. That the researchers treated “physically active” as a yes/no category, and how they categorized individuals, could be criticized, but this was done for pragmatic reasons, as a variety of means of assessing physical activity were used across the studies. It is unlikely that the findings would have changed if the authors had used a different method of defining physically active. Most of the studies included in the meta-analysis looked at one time point only; information about the influence of physical activity on weight changes over time in genetically susceptible individuals is only beginning to emerge. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001116. This study is further discussed in a PLoS Medicine Perspective by Lennert Veerman The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States A more worldwide view is given by the World Health Organization The UK National Health Service website gives information on physical activity guidelines for different age groups, while similar information can also be found from US sources
- Published
- 2011