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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 i...

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Autores principales: Panoutsopoulou, Kalliope, Metrustry, Sarah, Doherty, Sally A, Laslett, Laura L, Maciewicz, Rose A, Hart, Deborah J, Zhang, Weiya, Muir, Kenneth R, Wheeler, Margaret, Cooper, Cyrus, Spector, Tim D, Cicuttini, Flavia M, Jones, Graeme, Arden, Nigel K, Doherty, Michael, Zeggini, Eleftheria, Valdes, Ana M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251538/
https://www.ncbi.nlm.nih.gov/pubmed/23921993
http://dx.doi.org/10.1136/annrheumdis-2013-203772
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author Panoutsopoulou, Kalliope
Metrustry, Sarah
Doherty, Sally A
Laslett, Laura L
Maciewicz, Rose A
Hart, Deborah J
Zhang, Weiya
Muir, Kenneth R
Wheeler, Margaret
Cooper, Cyrus
Spector, Tim D
Cicuttini, Flavia M
Jones, Graeme
Arden, Nigel K
Doherty, Michael
Zeggini, Eleftheria
Valdes, Ana M
author_facet Panoutsopoulou, Kalliope
Metrustry, Sarah
Doherty, Sally A
Laslett, Laura L
Maciewicz, Rose A
Hart, Deborah J
Zhang, Weiya
Muir, Kenneth R
Wheeler, Margaret
Cooper, Cyrus
Spector, Tim D
Cicuttini, Flavia M
Jones, Graeme
Arden, Nigel K
Doherty, Michael
Zeggini, Eleftheria
Valdes, Ana M
author_sort Panoutsopoulou, Kalliope
collection PubMed
description 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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spelling pubmed-42515382014-12-04 The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study Panoutsopoulou, Kalliope Metrustry, Sarah Doherty, Sally A Laslett, Laura L Maciewicz, Rose A Hart, Deborah J Zhang, Weiya Muir, Kenneth R Wheeler, Margaret Cooper, Cyrus Spector, Tim D Cicuttini, Flavia M Jones, Graeme Arden, Nigel K Doherty, Michael Zeggini, Eleftheria Valdes, Ana M Ann Rheum Dis Clinical and Epidemiological Research 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. BMJ Publishing Group 2014-12 2013-08-06 /pmc/articles/PMC4251538/ /pubmed/23921993 http://dx.doi.org/10.1136/annrheumdis-2013-203772 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Clinical and Epidemiological Research
Panoutsopoulou, Kalliope
Metrustry, Sarah
Doherty, Sally A
Laslett, Laura L
Maciewicz, Rose A
Hart, Deborah J
Zhang, Weiya
Muir, Kenneth R
Wheeler, Margaret
Cooper, Cyrus
Spector, Tim D
Cicuttini, Flavia M
Jones, Graeme
Arden, Nigel K
Doherty, Michael
Zeggini, Eleftheria
Valdes, Ana M
The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
title The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
title_full The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
title_fullStr The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
title_full_unstemmed The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
title_short The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
title_sort effect of fto variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
topic Clinical and Epidemiological Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251538/
https://www.ncbi.nlm.nih.gov/pubmed/23921993
http://dx.doi.org/10.1136/annrheumdis-2013-203772
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