Physical activity attenuates the influence of FTO variants on obesity risk

A meta-analysis of 218,166 adults and 19,268 children

Tuomas O. Kilpeläinen, Lu Qi, Soren Brage, Stephen J. Sharp, Emily Sonestedt, Ellen Demerath, Tariq Ahmad, Samia Mora, Marika Kaakinen, Camilla Helene Sandholt, Christina Holzapfel, Christine S. Autenrieth, Elina Hyppönen, Stéphane Cauchi, Meian He, Zoltan Kutalik, Meena Kumari, Alena Stančáková, Karina Meidtner, Beverley Balkau & 96 others Jonathan T. Tan, Massimo Mangino, Nicholas J. Timpson, Yiqing Song, M. Carola Zillikens, Kathleen A. Jablonski, Melissa E. Garcia, Stefan Johansson, Jennifer L. Bragg-Gresham, Ying Wu, Jana V. van Vliet-Ostaptchouk, N. Charlotte Onland-Moret, Esther Zimmermann, Natalia V. Rivera, Toshiko Tanaka, Heather M. Stringham, Günther Silbernagel, Stavroula Kanoni, Mary F. Feitosa, Soren Snitker, Jonatan R. Ruiz, E. Metter, Maria Teresa Martinez Larrad, Mustafa Atalay, Maarit Hakanen, Najaf Amin, Christine Cavalcanti-Proença, Anders Grøntved, Göran Hallmans, John Olov Jansson, Johanna Kuusisto, Mika Kähönen, Pamela L. Lutsey, John J. Nolan, Luigi Palla, Oluf Pedersen, Louis Pérusse, Frida Renström, Robert A. Scott, Dmitry Shungin, Ulla Sovio, Tuija H. Tammelin, Tapani Rönnemaa, Timo A. Lakka, Matti Uusitupa, Manuel Serrano Rios, Luigi Ferrucci, Claude Bouchard, Aline Meirhaeghe, Mao Fu, Mark Walker, Ingrid B. Borecki, George V. Dedoussis, Andreas Fritsche, Claes Ohlsson, Michael Boehnke, Stefania Bandinelli, Cornelia M. van Duijn, Shah Ebrahim, Debbie A. Lawlor, Vilmundur Gudnason, Tamara B. Harris, Thorkild I.A. Sørensen, Karen L. Mohlke, Albert Hofman, André G. Uitterlinden, Jaakko Tuomilehto, Terho Lehtimäki, Olli Raitakari, Bo Isomaa, Pål R. Njølstad, Jose C. Florez, Simin Liu, Andy Ness, Timothy D. Spector, E. Shyong Tai, Philippe Froguel, Heiner Boeing, Markku Laakso, Michael Marmot, Sven Bergmann, Chris Power, Kay Tee Khaw, Daniel Chasman, Paul Ridker, Torben Hansen, Keri L. Monda, Thomas Illig, Marjo Riitta Järvelin, Nicholas J. Wareham, Frank B. Hu, Leif C. Groop, Marju Orho-Melander, Ulf Ekelund, Paul W. Franks, Ruth J.F. Loos

Research output: Contribution to journalArticle

276 Citations (Scopus)

Abstract

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (pinteraction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors' Summary.

Original languageEnglish (US)
Article numbere1001116
JournalPLoS Medicine
Volume8
Issue number11
DOIs
StatePublished - Jan 1 2011

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Meta-Analysis
Obesity
Exercise
Alleles
Odds Ratio
Proxy
Genes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Kilpeläinen, T. O., Qi, L., Brage, S., Sharp, S. J., Sonestedt, E., Demerath, E., ... Loos, R. J. F. (2011). Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children. PLoS Medicine, 8(11), [e1001116]. https://doi.org/10.1371/journal.pmed.1001116

Physical activity attenuates the influence of FTO variants on obesity risk : A meta-analysis of 218,166 adults and 19,268 children. / Kilpeläinen, Tuomas O.; Qi, Lu; Brage, Soren; Sharp, Stephen J.; Sonestedt, Emily; Demerath, Ellen; Ahmad, Tariq; Mora, Samia; Kaakinen, Marika; Sandholt, Camilla Helene; Holzapfel, Christina; Autenrieth, Christine S.; Hyppönen, Elina; Cauchi, Stéphane; He, Meian; Kutalik, Zoltan; Kumari, Meena; Stančáková, Alena; Meidtner, Karina; Balkau, Beverley; Tan, Jonathan T.; Mangino, Massimo; Timpson, Nicholas J.; Song, Yiqing; Zillikens, M. Carola; Jablonski, Kathleen A.; Garcia, Melissa E.; Johansson, Stefan; Bragg-Gresham, Jennifer L.; Wu, Ying; van Vliet-Ostaptchouk, Jana V.; Onland-Moret, N. Charlotte; Zimmermann, Esther; Rivera, Natalia V.; Tanaka, Toshiko; Stringham, Heather M.; Silbernagel, Günther; Kanoni, Stavroula; Feitosa, Mary F.; Snitker, Soren; Ruiz, Jonatan R.; Metter, E.; Larrad, Maria Teresa Martinez; Atalay, Mustafa; Hakanen, Maarit; Amin, Najaf; Cavalcanti-Proença, Christine; Grøntved, Anders; Hallmans, Göran; Jansson, John Olov; Kuusisto, Johanna; Kähönen, Mika; Lutsey, Pamela L.; Nolan, John J.; Palla, Luigi; Pedersen, Oluf; Pérusse, Louis; Renström, Frida; Scott, Robert A.; Shungin, Dmitry; Sovio, Ulla; Tammelin, Tuija H.; Rönnemaa, Tapani; Lakka, Timo A.; Uusitupa, Matti; Rios, Manuel Serrano; Ferrucci, Luigi; Bouchard, Claude; Meirhaeghe, Aline; Fu, Mao; Walker, Mark; Borecki, Ingrid B.; Dedoussis, George V.; Fritsche, Andreas; Ohlsson, Claes; Boehnke, Michael; Bandinelli, Stefania; van Duijn, Cornelia M.; Ebrahim, Shah; Lawlor, Debbie A.; Gudnason, Vilmundur; Harris, Tamara B.; Sørensen, Thorkild I.A.; Mohlke, Karen L.; Hofman, Albert; Uitterlinden, André G.; Tuomilehto, Jaakko; Lehtimäki, Terho; Raitakari, Olli; Isomaa, Bo; Njølstad, Pål R.; Florez, Jose C.; Liu, Simin; Ness, Andy; Spector, Timothy D.; Tai, E. Shyong; Froguel, Philippe; Boeing, Heiner; Laakso, Markku; Marmot, Michael; Bergmann, Sven; Power, Chris; Khaw, Kay Tee; Chasman, Daniel; Ridker, Paul; Hansen, Torben; Monda, Keri L.; Illig, Thomas; Järvelin, Marjo Riitta; Wareham, Nicholas J.; Hu, Frank B.; Groop, Leif C.; Orho-Melander, Marju; Ekelund, Ulf; Franks, Paul W.; Loos, Ruth J.F.

In: PLoS Medicine, Vol. 8, No. 11, e1001116, 01.01.2011.

Research output: Contribution to journalArticle

Kilpeläinen, TO, Qi, L, Brage, S, Sharp, SJ, Sonestedt, E, Demerath, E, Ahmad, T, Mora, S, Kaakinen, M, Sandholt, CH, Holzapfel, C, Autenrieth, CS, Hyppönen, E, Cauchi, S, He, M, Kutalik, Z, Kumari, M, Stančáková, A, Meidtner, K, Balkau, B, Tan, JT, Mangino, M, Timpson, NJ, Song, Y, Zillikens, MC, Jablonski, KA, Garcia, ME, Johansson, S, Bragg-Gresham, JL, Wu, Y, van Vliet-Ostaptchouk, JV, Onland-Moret, NC, Zimmermann, E, Rivera, NV, Tanaka, T, Stringham, HM, Silbernagel, G, Kanoni, S, Feitosa, MF, Snitker, S, Ruiz, JR, Metter, E, Larrad, MTM, Atalay, M, Hakanen, M, Amin, N, Cavalcanti-Proença, C, Grøntved, A, Hallmans, G, Jansson, JO, Kuusisto, J, Kähönen, M, Lutsey, PL, Nolan, JJ, Palla, L, Pedersen, O, Pérusse, L, Renström, F, Scott, RA, Shungin, D, Sovio, U, Tammelin, TH, Rönnemaa, T, Lakka, TA, Uusitupa, M, Rios, MS, Ferrucci, L, Bouchard, C, Meirhaeghe, A, Fu, M, Walker, M, Borecki, IB, Dedoussis, GV, Fritsche, A, Ohlsson, C, Boehnke, M, Bandinelli, S, van Duijn, CM, Ebrahim, S, Lawlor, DA, Gudnason, V, Harris, TB, Sørensen, TIA, Mohlke, KL, Hofman, A, Uitterlinden, AG, Tuomilehto, J, Lehtimäki, T, Raitakari, O, Isomaa, B, Njølstad, PR, Florez, JC, Liu, S, Ness, A, Spector, TD, Tai, ES, Froguel, P, Boeing, H, Laakso, M, Marmot, M, Bergmann, S, Power, C, Khaw, KT, Chasman, D, Ridker, P, Hansen, T, Monda, KL, Illig, T, Järvelin, MR, Wareham, NJ, Hu, FB, Groop, LC, Orho-Melander, M, Ekelund, U, Franks, PW & Loos, RJF 2011, 'Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children', PLoS Medicine, vol. 8, no. 11, e1001116. https://doi.org/10.1371/journal.pmed.1001116
Kilpeläinen, Tuomas O. ; Qi, Lu ; Brage, Soren ; Sharp, Stephen J. ; Sonestedt, Emily ; Demerath, Ellen ; Ahmad, Tariq ; Mora, Samia ; Kaakinen, Marika ; Sandholt, Camilla Helene ; Holzapfel, Christina ; Autenrieth, Christine S. ; Hyppönen, Elina ; Cauchi, Stéphane ; He, Meian ; Kutalik, Zoltan ; Kumari, Meena ; Stančáková, Alena ; Meidtner, Karina ; Balkau, Beverley ; Tan, Jonathan T. ; Mangino, Massimo ; Timpson, Nicholas J. ; Song, Yiqing ; Zillikens, M. Carola ; Jablonski, Kathleen A. ; Garcia, Melissa E. ; Johansson, Stefan ; Bragg-Gresham, Jennifer L. ; Wu, Ying ; van Vliet-Ostaptchouk, Jana V. ; Onland-Moret, N. Charlotte ; Zimmermann, Esther ; Rivera, Natalia V. ; Tanaka, Toshiko ; Stringham, Heather M. ; Silbernagel, Günther ; Kanoni, Stavroula ; Feitosa, Mary F. ; Snitker, Soren ; Ruiz, Jonatan R. ; Metter, E. ; Larrad, Maria Teresa Martinez ; Atalay, Mustafa ; Hakanen, Maarit ; Amin, Najaf ; Cavalcanti-Proença, Christine ; Grøntved, Anders ; Hallmans, Göran ; Jansson, John Olov ; Kuusisto, Johanna ; Kähönen, Mika ; Lutsey, Pamela L. ; Nolan, John J. ; Palla, Luigi ; Pedersen, Oluf ; Pérusse, Louis ; Renström, Frida ; Scott, Robert A. ; Shungin, Dmitry ; Sovio, Ulla ; Tammelin, Tuija H. ; Rönnemaa, Tapani ; Lakka, Timo A. ; Uusitupa, Matti ; Rios, Manuel Serrano ; Ferrucci, Luigi ; Bouchard, Claude ; Meirhaeghe, Aline ; Fu, Mao ; Walker, Mark ; Borecki, Ingrid B. ; Dedoussis, George V. ; Fritsche, Andreas ; Ohlsson, Claes ; Boehnke, Michael ; Bandinelli, Stefania ; van Duijn, Cornelia M. ; Ebrahim, Shah ; Lawlor, Debbie A. ; Gudnason, Vilmundur ; Harris, Tamara B. ; Sørensen, Thorkild I.A. ; Mohlke, Karen L. ; Hofman, Albert ; Uitterlinden, André G. ; Tuomilehto, Jaakko ; Lehtimäki, Terho ; Raitakari, Olli ; Isomaa, Bo ; Njølstad, Pål R. ; Florez, Jose C. ; Liu, Simin ; Ness, Andy ; Spector, Timothy D. ; Tai, E. Shyong ; Froguel, Philippe ; Boeing, Heiner ; Laakso, Markku ; Marmot, Michael ; Bergmann, Sven ; Power, Chris ; Khaw, Kay Tee ; Chasman, Daniel ; Ridker, Paul ; Hansen, Torben ; Monda, Keri L. ; Illig, Thomas ; Järvelin, Marjo Riitta ; Wareham, Nicholas J. ; Hu, Frank B. ; Groop, Leif C. ; Orho-Melander, Marju ; Ekelund, Ulf ; Franks, Paul W. ; Loos, Ruth J.F. / Physical activity attenuates the influence of FTO variants on obesity risk : A meta-analysis of 218,166 adults and 19,268 children. In: PLoS Medicine. 2011 ; Vol. 8, No. 11.
@article{377ff38c687244afa1b53bb1a188f307,
title = "Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children",
abstract = "Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25{\%} of adults and 13{\%} of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95{\%} CI 1.20-1.26), but PA attenuated this effect (pinteraction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95{\%} CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95{\%} CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27{\%} in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors' Summary.",
author = "Kilpel{\"a}inen, {Tuomas O.} and Lu Qi and Soren Brage and Sharp, {Stephen J.} and Emily Sonestedt and Ellen Demerath and Tariq Ahmad and Samia Mora and Marika Kaakinen and Sandholt, {Camilla Helene} and Christina Holzapfel and Autenrieth, {Christine S.} and Elina Hypp{\"o}nen and St{\'e}phane Cauchi and Meian He and Zoltan Kutalik and Meena Kumari and Alena Stanč{\'a}kov{\'a} and Karina Meidtner and Beverley Balkau and Tan, {Jonathan T.} and Massimo Mangino and Timpson, {Nicholas J.} and Yiqing Song and Zillikens, {M. Carola} and Jablonski, {Kathleen A.} and Garcia, {Melissa E.} and Stefan Johansson and Bragg-Gresham, {Jennifer L.} and Ying Wu and {van Vliet-Ostaptchouk}, {Jana V.} and Onland-Moret, {N. Charlotte} and Esther Zimmermann and Rivera, {Natalia V.} and Toshiko Tanaka and Stringham, {Heather M.} and G{\"u}nther Silbernagel and Stavroula Kanoni and Feitosa, {Mary F.} and Soren Snitker and Ruiz, {Jonatan R.} and E. Metter and Larrad, {Maria Teresa Martinez} and Mustafa Atalay and Maarit Hakanen and Najaf Amin and Christine Cavalcanti-Proen{\cc}a and Anders Gr{\o}ntved and G{\"o}ran Hallmans and Jansson, {John Olov} and Johanna Kuusisto and Mika K{\"a}h{\"o}nen and Lutsey, {Pamela L.} and Nolan, {John J.} and Luigi Palla and Oluf Pedersen and Louis P{\'e}russe and Frida Renstr{\"o}m and Scott, {Robert A.} and Dmitry Shungin and Ulla Sovio and Tammelin, {Tuija H.} and Tapani R{\"o}nnemaa and Lakka, {Timo A.} and Matti Uusitupa and Rios, {Manuel Serrano} and Luigi Ferrucci and Claude Bouchard and Aline Meirhaeghe and Mao Fu and Mark Walker and Borecki, {Ingrid B.} and Dedoussis, {George V.} and Andreas Fritsche and Claes Ohlsson and Michael Boehnke and Stefania Bandinelli and {van Duijn}, {Cornelia M.} and Shah Ebrahim and Lawlor, {Debbie A.} and Vilmundur Gudnason and Harris, {Tamara B.} and S{\o}rensen, {Thorkild I.A.} and Mohlke, {Karen L.} and Albert Hofman and Uitterlinden, {Andr{\'e} G.} and Jaakko Tuomilehto and Terho Lehtim{\"a}ki and Olli Raitakari and Bo Isomaa and Nj{\o}lstad, {P{\aa}l R.} and Florez, {Jose C.} and Simin Liu and Andy Ness and Spector, {Timothy D.} and Tai, {E. Shyong} and Philippe Froguel and Heiner Boeing and Markku Laakso and Michael Marmot and Sven Bergmann and Chris Power and Khaw, {Kay Tee} and Daniel Chasman and Paul Ridker and Torben Hansen and Monda, {Keri L.} and Thomas Illig and J{\"a}rvelin, {Marjo Riitta} and Wareham, {Nicholas J.} and Hu, {Frank B.} and Groop, {Leif C.} and Marju Orho-Melander and Ulf Ekelund and Franks, {Paul W.} and Loos, {Ruth J.F.}",
year = "2011",
month = "1",
day = "1",
doi = "10.1371/journal.pmed.1001116",
language = "English (US)",
volume = "8",
journal = "PLoS Medicine",
issn = "1549-1277",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Physical activity attenuates the influence of FTO variants on obesity risk

T2 - A meta-analysis of 218,166 adults and 19,268 children

AU - Kilpeläinen, Tuomas O.

AU - Qi, Lu

AU - Brage, Soren

AU - Sharp, Stephen J.

AU - Sonestedt, Emily

AU - Demerath, Ellen

AU - Ahmad, Tariq

AU - Mora, Samia

AU - Kaakinen, Marika

AU - Sandholt, Camilla Helene

AU - Holzapfel, Christina

AU - Autenrieth, Christine S.

AU - Hyppönen, Elina

AU - Cauchi, Stéphane

AU - He, Meian

AU - Kutalik, Zoltan

AU - Kumari, Meena

AU - Stančáková, Alena

AU - Meidtner, Karina

AU - Balkau, Beverley

AU - Tan, Jonathan T.

AU - Mangino, Massimo

AU - Timpson, Nicholas J.

AU - Song, Yiqing

AU - Zillikens, M. Carola

AU - Jablonski, Kathleen A.

AU - Garcia, Melissa E.

AU - Johansson, Stefan

AU - Bragg-Gresham, Jennifer L.

AU - Wu, Ying

AU - van Vliet-Ostaptchouk, Jana V.

AU - Onland-Moret, N. Charlotte

AU - Zimmermann, Esther

AU - Rivera, Natalia V.

AU - Tanaka, Toshiko

AU - Stringham, Heather M.

AU - Silbernagel, Günther

AU - Kanoni, Stavroula

AU - Feitosa, Mary F.

AU - Snitker, Soren

AU - Ruiz, Jonatan R.

AU - Metter, E.

AU - Larrad, Maria Teresa Martinez

AU - Atalay, Mustafa

AU - Hakanen, Maarit

AU - Amin, Najaf

AU - Cavalcanti-Proença, Christine

AU - Grøntved, Anders

AU - Hallmans, Göran

AU - Jansson, John Olov

AU - Kuusisto, Johanna

AU - Kähönen, Mika

AU - Lutsey, Pamela L.

AU - Nolan, John J.

AU - Palla, Luigi

AU - Pedersen, Oluf

AU - Pérusse, Louis

AU - Renström, Frida

AU - Scott, Robert A.

AU - Shungin, Dmitry

AU - Sovio, Ulla

AU - Tammelin, Tuija H.

AU - Rönnemaa, Tapani

AU - Lakka, Timo A.

AU - Uusitupa, Matti

AU - Rios, Manuel Serrano

AU - Ferrucci, Luigi

AU - Bouchard, Claude

AU - Meirhaeghe, Aline

AU - Fu, Mao

AU - Walker, Mark

AU - Borecki, Ingrid B.

AU - Dedoussis, George V.

AU - Fritsche, Andreas

AU - Ohlsson, Claes

AU - Boehnke, Michael

AU - Bandinelli, Stefania

AU - van Duijn, Cornelia M.

AU - Ebrahim, Shah

AU - Lawlor, Debbie A.

AU - Gudnason, Vilmundur

AU - Harris, Tamara B.

AU - Sørensen, Thorkild I.A.

AU - Mohlke, Karen L.

AU - Hofman, Albert

AU - Uitterlinden, André G.

AU - Tuomilehto, Jaakko

AU - Lehtimäki, Terho

AU - Raitakari, Olli

AU - Isomaa, Bo

AU - Njølstad, Pål R.

AU - Florez, Jose C.

AU - Liu, Simin

AU - Ness, Andy

AU - Spector, Timothy D.

AU - Tai, E. Shyong

AU - Froguel, Philippe

AU - Boeing, Heiner

AU - Laakso, Markku

AU - Marmot, Michael

AU - Bergmann, Sven

AU - Power, Chris

AU - Khaw, Kay Tee

AU - Chasman, Daniel

AU - Ridker, Paul

AU - Hansen, Torben

AU - Monda, Keri L.

AU - Illig, Thomas

AU - Järvelin, Marjo Riitta

AU - Wareham, Nicholas J.

AU - Hu, Frank B.

AU - Groop, Leif C.

AU - Orho-Melander, Marju

AU - Ekelund, Ulf

AU - Franks, Paul W.

AU - Loos, Ruth J.F.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (pinteraction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors' Summary.

AB - Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (pinteraction = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity. Please see later in the article for the Editors' Summary.

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U2 - 10.1371/journal.pmed.1001116

DO - 10.1371/journal.pmed.1001116

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VL - 8

JO - PLoS Medicine

JF - PLoS Medicine

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