University of Groningen Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk

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 [r.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 FTO6PA 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 (A2) 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. Physical Activity Attenuates Influence of FTO PLoS Medicine | www.plosmedicine. org 2 November 2011 | Volume 8 | Issue 11 | e1001116 Citation: Kilpeläinen TO, Qi L, Brage S, Sharp SJ, Sonestedt E, et al. (2011) Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A MetaAnalysis of 218,166 Adults and 19,268 Children. PLoS Med 8(11): e1001116. doi:10.1371/journal.pmed. 1001116 Academic Editor: Cathryn Lewis, Kings College London, United Kingdom Received April 21, 2011; Accepted September 23, 2011; Published November 1, 2011 Copyright: 2011 Loos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: There was no specific funding for this project/meta-analysis. Funding sources for the individual authors and for the studies included in the metaanalysis are listed in Text S2. The publication is the work of the authors, and the views in this paper are not necessarily those of any funding body. No funding body has dictated how analyses were undertaken or results interpreted, and Ruth Loos acts as guarantor for the contents. Competing Interests: JJN has, since January 2011, been employed at Steno Diabetes Centre, a legally independent clinical and research body, which is wholly owned by Novo Nordisk. In relation to his contribution to this manuscript (through the RISC study), all of this work pre-dates his appointment to his current position. All other authors have declared that no competing interests exist. Abbreviations: BMI, body mass index; OR, odds ratio; PA, physical activity; SNP, single nucleotide polymorphism. * E-mail: luqi@hsph.harvard. edu (LQ); paul.franks@med.lu. se (PWF); ruth.loos@mrc-epid.cam. ac.uk (RJFL) Physical Activity Attenuates Influence of FTO PLoS Medicine | www.plosmedicine. org 3 November 2011 | Volume 8 | Issue 11 | e1001116