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The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study

The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
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.
0003-4967
2082-2086
Pannoutsopoulou, K.
7a821c3b-5c52-40ae-bf55-badf8411f0ff
Metrustry, S.
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Doherty, S.
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Laslett, L.L.
afb259f5-8521-4ba7-b3bc-01d13932e615
Maciewicz, R.A.
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Hart, D.J.
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Zhang, W.
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Muir, K.R.
639993b9-774f-4f73-a253-458d927c1f6a
Wheeler, M.
cca02688-13c2-477f-ad2d-12e39e8bac3e
Cooper, C.
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Spector, T.D.
87d1f285-3f22-4c9a-b006-d65cfda6d3e0
Cicuttini, F.M.
ee18e80f-a7d0-4d8e-8686-97824db606cb
Jones, G.
6f771ff0-5f71-4709-be07-8bcf83871a7c
Arden, N.K.
23af958d-835c-4d79-be54-4bbe4c68077f
Doherty, M.
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Zeggini, E.
65e46634-d486-4a4e-8527-a81388142a70
Valdes, A.M.
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Pannoutsopoulou, K.
7a821c3b-5c52-40ae-bf55-badf8411f0ff
Metrustry, S.
e0cac118-a799-49ab-b1d1-28c06e11c425
Doherty, S.
7cff3c24-468e-43d5-ab57-df0dece397a5
Laslett, L.L.
afb259f5-8521-4ba7-b3bc-01d13932e615
Maciewicz, R.A.
65decc35-5b04-4751-aeb3-64ab1934ba4f
Hart, D.J.
00e78191-ce14-4b5f-a720-9f1bb51b2b62
Zhang, W.
1c80d4f2-4ba8-41f6-85a6-a76a4d65dc9b
Muir, K.R.
639993b9-774f-4f73-a253-458d927c1f6a
Wheeler, M.
cca02688-13c2-477f-ad2d-12e39e8bac3e
Cooper, C.
e05f5612-b493-4273-9b71-9e0ce32bdad6
Spector, T.D.
87d1f285-3f22-4c9a-b006-d65cfda6d3e0
Cicuttini, F.M.
ee18e80f-a7d0-4d8e-8686-97824db606cb
Jones, G.
6f771ff0-5f71-4709-be07-8bcf83871a7c
Arden, N.K.
23af958d-835c-4d79-be54-4bbe4c68077f
Doherty, M.
3ccd8b47-e119-4f38-b813-08e9036a9ff3
Zeggini, E.
65e46634-d486-4a4e-8527-a81388142a70
Valdes, A.M.
9a213e37-af13-4e57-bb0f-9ff0a43dbffc

Pannoutsopoulou, K., Metrustry, S., Doherty, S., Laslett, L.L., Maciewicz, R.A., Hart, D.J., Zhang, W., Muir, K.R., Wheeler, M., Cooper, C., Spector, T.D., Cicuttini, F.M., Jones, G., Arden, N.K., Doherty, M., Zeggini, E. and Valdes, A.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, 73 (12), 2082-2086. (doi:10.1136/annrheumdis-2013-203772). (PMID:23921993)

Record type: Article

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.

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More information

Accepted/In Press date: 15 July 2013
e-pub ahead of print date: 6 August 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 373545
URI: http://eprints.soton.ac.uk/id/eprint/373545
ISSN: 0003-4967
PURE UUID: 06f99bad-ee62-462d-a676-97bf577c2c55
ORCID for C. Cooper: ORCID iD orcid.org/0000-0003-3510-0709

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Date deposited: 21 Jan 2015 14:41
Last modified: 28 Oct 2023 01:42

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Contributors

Author: K. Pannoutsopoulou
Author: S. Metrustry
Author: S. Doherty
Author: L.L. Laslett
Author: R.A. Maciewicz
Author: D.J. Hart
Author: W. Zhang
Author: K.R. Muir
Author: M. Wheeler
Author: C. Cooper ORCID iD
Author: T.D. Spector
Author: F.M. Cicuttini
Author: G. Jones
Author: N.K. Arden
Author: M. Doherty
Author: E. Zeggini
Author: A.M. Valdes

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