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The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index : a mendelian randomisation study
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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 ISSN 0003-4967.
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Official URL: http://dx.doi.org/10.1136/annrheumdis-2013-203772
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 | ||||||||||
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Subjects: | R Medicine > RA Public aspects of medicine | ||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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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: |
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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 (Creative Commons) | ||||||||||
Date of first compliant deposit: | 28 December 2015 | ||||||||||
Date of first compliant Open Access: | 28 December 2015 | ||||||||||
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) | ||||||||||
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