Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.

Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. Estonian Genome Center, University of Tartu, Tartu, Estonia. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York, USA. Icelandic Heart Association, Kopavogur, Iceland. University of Icelandic, Reykajvik, Iceland. The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark. Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK. Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. School of Medicine, University of Tampere, Tampere, Finland. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Department of Medicine I, Ludwig-Maximilians-University, Munich, Germany. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner site Munich Heart Alliance, Munich, Germany. Karolinska Institutet, Institute of Environmental Medicine, Unit of Cardiovascular Epidemiology, Stockholm, Sweden. Department of Internal Medicine, Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland. MRC Unit for Lifelong Health and Ageing, University College London, London, UK. Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany. QIMR Berghofer Medical Research Institute, Brisbane, Australia. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. Institute of Regional Health Services Research and Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. Danish Cancer Society Research Centre, Copenhagen, Denmark. Diabetes Prevention Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. Department of General Practice and Primary Health Care, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland. Folkhälsan Research Centre, Helsinki, Finland. Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland. Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. Department of Genetic, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Durrer Center for Cardiogenetic Research, ICIN-Neterlands Heart Institute, Utrecht, The Netherlands. Department of Epidemiology and Public Health, University College London, London, UK. ISER, University of Essex, Colchester, UK. Inserm, U744, Institut Pasteur de Lille, University Lille Nord de France, Lille, France. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. Centre for Vascular Prevention, Danube-University Krems, Krems, Austria. Instituto de Investigacion Sanitaria del Hospital Universario LaPaz (IdiPAZ), Madrid, Spain. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia. School of Social and Community Medicine, University of Bristol, Bristol, UK. BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, UK. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. Institute of Cardiovascular Science, University College London, London, UK. Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, USA. Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. Synlab Academy, Synlab Services GmbH, Mannheim, Germany. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Department of Child and Adolescent Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands. Department of Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands. Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden. Novo Nordisk Foundation Centre for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.

Obesity reviews : an official journal of the International Association for the Study of Obesity. 2015;(4):327-340

Abstract

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.

Methodological quality

Publication Type : Meta-Analysis

Metadata

MeSH terms : Adiposity ; Proteins