The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a Mendelian randomisation study.
OBJECTIVE
Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information.


METHODS
5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA.


RESULTS
In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10(-7)). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA.


CONCLUSIONS
Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Kalliope
K
Panoutsopoulou
Department of Twin Research, King's College London, St Thomas' Hospital, London, UK.
Sarah
S
Metrustry
Academic Rheumatology, Nottingham City Hospital, Nottingham, UK.
Sally A
SA
Doherty
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
Laura L
LL
Laslett
Respiratory & Inflammation iMed, AstraZeneca, Mölndal, Sweden.
Rose A
RA
Maciewicz
Department of Twin Research, King's College London, St Thomas' Hospital, London, UK.
Deborah J
DJ
Hart
Academic Rheumatology, Nottingham City Hospital, Nottingham, UK.
Weiya
W
Zhang
Centre for Epidemiology, Institute of Population Health, The Medical School, University of Manchester, Manchester, UK Health Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, UK.
Kenneth R
KR
Muir
Academic Rheumatology, Nottingham City Hospital, Nottingham, UK.
Margaret
M
Wheeler
NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.
Cyrus
C
Cooper
Department of Twin Research, King's College London, St Thomas' Hospital, London, UK.
Tim D
TD
Spector
Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Australia.
Flavia M
FM
Cicuttini
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.
Graeme
G
Jones
NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.
Nigel K
NK
Arden
Academic Rheumatology, Nottingham City Hospital, Nottingham, UK.
Michael
M
Doherty
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Eleftheria
E
Zeggini
Department of Twin Research, King's College London, St Thomas' Hospital, London, UK Academic Rheumatology, Nottingham City Hospital, Nottingham, UK.
Ana M
AM
Valdes
D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D016022:Case-Control Studies; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D015207:Osteoarthritis, Hip / Q000235:genetics*; D020370:Osteoarthritis, Knee / Q000235:genetics*; D050177:Overweight / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*
D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human
Epidemiology; Gene Polymorphism; Knee Osteoarthritis; Osteoarthritis