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 BalkauJonathan 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, Jeffery 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

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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
Issue number11
StatePublished - Nov 2011

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