arcOGEN Consortium (Including: Panoutsopoulou, Kalliope, Metrustry, Sarah, Doherty, Sally A., Laslett, Laura L., Maciewicz, Rose A., Hart, Deborah J., Zhang, Weiya, Muir, Kenneth, Wheeler, Margaret, Cooper, Cyrus, Spector, T. D., Cicuttini, Flavia M., Jones, Graeme, Arden, N., Doherty, Michael, Zeggini, Eleftheria and Valdes, Ana M.). (2013) The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index : a mendelian randomisation study. Annals of the rheumatic diseases, Volume 73 (Number 12). pp. 2082-2086. doi:10.1136/annrheumdis-2013-203772

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Abstract

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.

Item Type:	Journal Article
Subjects:	R Medicine > RA Public aspects of medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Osteoarthritis, Body mass index -- Health aspects
Journal or Publication Title:	Annals of the rheumatic diseases
Publisher:	BMJ Group
ISSN:	0003-4967
Official Date:	6 August 2013
Dates:	Date Event 6 August 2013 Available 15 July 2013 Accepted 21 June 2013 Modified 12 April 2013 Submitted
Volume:	Volume 73
Number:	Number 12
Page Range:	pp. 2082-2086
DOI:	10.1136/annrheumdis-2013-203772
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Seventh Framework Programme (European Commission) (FP7), Tasmanian Community Fund, Masonic Centenary Medical Research Foundation, Royal Hobart Hospital Research Foundation, University of Tasmania
Grant number:	200800 (FP7)
Adapted As:

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