Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.
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.
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark.
E
E
Zimmermann
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark.
L H
LH
Ängquist
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
S S
SS
Mirza
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
J H
JH
Zhao
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
D I
DI
Chasman
Estonian Genome Center, University of Tartu, Tartu, Estonia.
K
K
Fischer
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York, USA.
Q
Q
Qi
Icelandic Heart Association, Kopavogur, Iceland.|University of Icelandic, Reykajvik, Iceland.
A V
AV
Smith
The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
M
M
Thinggaard
Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
M N
MN
Jarczok
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.
M A
MA
Nalls
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
S
S
Trompet
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
N J
NJ
Timpson
Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany.
B
B
Schmidt
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
A U
AU
Jackson
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.|School of Medicine, University of Tampere, Tampere, Finland.
L P
LP
Lyytikäinen
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
N
N
Verweij
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.
M
M
Mueller-Nurasyid
Karolinska Institutet, Institute of Environmental Medicine, Unit of Cardiovascular Epidemiology, Stockholm, Sweden.
M
M
Vikström
Department of Internal Medicine, Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
P
P
Marques-Vidal
MRC Unit for Lifelong Health and Ageing, University College London, London, UK.
A
A
Wong
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.
K
K
Meidtner
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
R P
RP
Middelberg
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
R J
RJ
Strawbridge
The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
L
L
Christiansen
Institute of Regional Health Services Research and Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.
K O
KO
Kyvik
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
A
A
Hamsten
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
T
T
Jääskeläinen
Danish Cancer Society Research Centre, Copenhagen, Denmark.
A
A
Tjønneland
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.
J G
JG
Eriksson
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
J B
JB
Whitfield
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.
H
H
Boeing
MRC Unit for Lifelong Health and Ageing, University College London, London, UK.
R
R
Hardy
Department of Internal Medicine, Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
P
P
Vollenweider
Karolinska Institutet, Institute of Environmental Medicine, Unit of Cardiovascular Epidemiology, Stockholm, Sweden.
K
K
Leander
Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner site Munich Heart Alliance, Munich, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
A
A
Peters
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|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.
P
P
van der Harst
Department of Epidemiology and Public Health, University College London, London, UK.|ISER, University of Essex, Colchester, UK.
M
M
Kumari
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.|School of Medicine, University of Tampere, Tampere, Finland.
T
T
Lehtimäki
Inserm, U744, Institut Pasteur de Lille, University Lille Nord de France, Lille, France.
A
A
Meirhaeghe
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.
J
J
Tuomilehto
Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany.
K-H
KH
Jöckel
School of Social and Community Medicine, University of Bristol, Bristol, UK.
Y
Y
Ben-Shlomo
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, UK.
N
N
Sattar
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
S E
SE
Baumeister
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
G Davey
GD
Smith
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.|Institute of Cardiovascular Science, University College London, London, UK.
J P
JP
Casas
Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.
D K
DK
Houston
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.
W
W
März
The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.|Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.|Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
K
K
Christensen
Icelandic Heart Association, Kopavogur, Iceland.|University of Icelandic, Reykajvik, Iceland.
V
V
Gudnason
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
F B
FB
Hu
Estonian Genome Center, University of Tartu, Tartu, Estonia.
A
A
Metspalu
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
P M
PM
Ridker
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
N J
NJ
Wareham
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.|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.
R J F
RJF
Loos
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.|Department of Child and Adolescent Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands.|Department of Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands.
H
H
Tiemeier
Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
E
E
Sonestedt
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark.|MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.|Novo Nordisk Foundation Centre for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
T I A
TIA
Sørensen
D050154:Adiposity / Q000235:genetics*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D009765:Obesity / Q000235:genetics / Q000401:mortality*; D064887:Observational Studies as Topic; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D055105:Waist Circumference
D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human
FTO; meta-analysis; mortality; obesity