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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 [r(2)>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 (p(interaction) ?=?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.

SUBMITTER: Kilpelainen TO

PROVIDER: S-EPMC3206047 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

PLoS medicine 20111101 11

<h4>Background</h4>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).<h4 ...[more]

PMID: 22069379

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Project description:BackgroundVariants in the FTO gene have been associated with obesity in children, but this association has not been shown with other biomarkers. We assessed the association of 52 FTO polymorphisms, spanning the whole gene, with obesity and estimated the influence of these polymorphisms on anthropometric, clinical and metabolic parameters as well as inflammation and cardiovascular disease (CVD) risk biomarkers among Spanish children.MethodsA multicentre case-control study was conducted in 534 children (292 obese and 242 with normal-BMI). Anthropometric, clinical, metabolic, inflammation and CVD risk markers were compared using the Student's t-test for unpaired samples. The genotype relative risk was assessed by comparing the obese and normal-BMI group, calculating the odds ratio. The association of each SNP with phenotypic parameters was analysed using either logistic or linear regression analysis.ResultsAll anthropometric, clinical and metabolic factors as well as inflammatory and CVD risk biomarkers were higher in the obese than in the normal-BMI group, except adiponectin and HDL-c that were lower, and glucose, LDL-c, and metalloproteinase-9 that did not show difference. Four polymorphisms (rs9935401, rs9939609, rs9928094 and rs9930333) were positively associated with obesity and in linkage disequilibrium between each other; the haplotype including the risk alleles of these polymorphisms showed a high risk for obesity. The rs8061518 was negatively associated with obesity and the haplotype including this SNP and rs3826169, rs17818902 and rs7190053 showed a decreased risk for obesity. Additionally, the rs8061518 was associated with weight, diastolic blood pressure, insulin, homeostatic model assessment of insulin resistance, leptin, and active plasminogen inhibitor activator-1 after sex and age adjustment; however, after an additional BMI adjustment, this polymorphism remained associated only with leptin.ConclusionsWe validated the previous reported association of genetic variability in intron 1 of the FTO gene with the risk of obesity and found no association with other related traits in this region of the gene. We have observed strong statistical evidence for an association of rs8061518 in intron 3 of the gene with decreased risk of obesity and low concentration of leptin.

Project description:The metabolic risks associated with obesity are greater for South Asian populations compared with White or other ethnic groups, and levels of obesity in childhood are known to track into adulthood. Tackling obesity in South Asians is therefore a high priority. The rationale for this systematic review is the suggestion that there may be differential effectiveness in diet and physical activity interventions in South Asian populations compared with other ethnicities. The research territory of the present review is an emergent, rather than mature, field of enquiry, but is urgently needed. Thus the aim of this systematic review and meta-analysis was to assess the effectiveness of diet and physical activity interventions to prevent or treat obesity in South Asians living in or outside of South Asia and to describe the characteristics of effective interventions.Systematic review of any type of lifestyle intervention, of any length of follow-up that reported any anthropometric measure for children or adults of South Asian ethnicity. There was no restriction on the type of comparator; randomised controlled trials, controlled clinical trials, and before-after studies were included. A comprehensive search strategy was implemented in five electronic databases: ASSIA, Cochrane Controlled Trials Register, Embase, Medline and Social Sciences Citation Index. The search was limited to English language abstracts published between January 2006 and January 2014. References were screened; data extraction and quality assessment were carried out by two reviewers. RESULTS are presented in narrative synthesis and meta-analysis.Twenty-nine studies were included, seven children, 21 adult and one mixed age. No studies in children under six were identified. Sixteen studies were conducted in South Asia, ten in Europe and three in USA. Effective or promising trials include physical activity interventions in South Asian men in Norway and South Asian school-children in the UK. A home-based, family-orientated diet and physical activity intervention improved obesity outcomes in South Asian adults in the UK, when adjusted for baseline differences. Meta-analyses of interventions in children showed no significant difference between intervention and control for body mass index or waist circumference. Meta-analyses of adult interventions showed significant improvement in weight in data from two trials adjusted for baseline differences (mean difference -1.82 kgs, 95% confidence interval -2.48 to -1.16) and in unadjusted data from three trials following sensitivity analysis (mean difference -1.20 kgs, 95% confidence interval -2.23 to -0.17). Meta-analyses showed no significant differences in body mass index and waist circumference for adults. Twenty of 24 intervention groups showed improvements in adult body mass index from baseline to follow-up; average change in high quality studies (n = 7) ranged from 0.31 to -0.8 kg/m2. There was no evidence that interventions were more or less effective according to whether the intervention was set in South Asia or not, or by socio-economic status.Meta-analysis of a limited number of controlled trials found an unclear picture of the effects of interventions on body mass index for South Asian children. Meta-analyses of a limited number of controlled trials showed significant improvement in weight for adults but no significant differences in body mass index and waist circumference. One high quality study in South Asian children found that a school-based physical activity intervention that was delivered within the normal school day which was culturally sensitive, was effective. There is also evidence of culturally appropriate approaches to, and characteristics of, effective interventions in adults which we believe could be transferred and used to develop effective interventions in children.

Project description:BACKGROUND:Meta-analysis of genome-wide association studies identified obesity-related genetic variants. Due to the pleiotropic effects of related phenotypes, we tested six of these obesity-related genetic variants for their association with physical activity: fat mass and obesity-associated (FTO)(rs9939609)T>A, potassium channel tetramerization domain containing (KCTD15) (rs11084753)G>A, melanocortin receptor4 (MC4R)(rs17782313)T>C, neuronal growth regulator 1 (NEGR1)(rs2815752)A>G, SH2B adapter protein 1 (SH2B1)(rs7498665)A>G, and transmembrane protein18 (TMEM18)(rs6548238)C>T. METHOD:European-American women (n = 263) and men (n = 229) (23.5 ± 0.3 years, 24.6 ± 0.2 kg/m2) were genotyped and completed the Paffenbarger physical activity Questionnaire. Physical activity volume in metabolic energy equivalents [MET]-hour/week was derived from the summed time spent (hour/week) times the given MET value for vigorous, moderate, and light intensity physical activity, and sitting and sleeping, respectively. Multivariable adjusted [(age, sex, and body mass index (BMI)] linear regression tested associations among genotype (dominant/recessive model) and the log of physical activity volume. RESULT:MC4R (rs17782313)T>C explained 1.1 % (p = 0.02), TMEM18(rs6548238)C>T 1.2 % (p = 0.01), and SH2B1 (rs7498665)A>G 0.6 % (p = 0.08) of the variability in physical activity volume. Subjects with the MC4R C allele spent 3.5 % less MET-hour/week than those with the TT genotype (p = 0.02). Subjects with the TMEM18 T allele spent 4.1 % less MET-hour/week than those with the CC genotype (p = 0.01). Finally, subjects with the SH2B1 GG genotype spent 3.6 % less MET-hour/week than A allele carriers (p = 0.08). CONCLUSION:Our findings suggest a shared genetic influence among some obesity-related gene loci and physical activity phenotypes that should be explored further. Physical activity volume differences by genotype have public health importance equating to 11-13 lb weight difference annually.

Dataset Information

Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.

Publications

Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.

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