Physical Activity and the Association of Common FTO Gene Variants With Body Mass Index and Obesity

Department of Medicine, University of Maryland, Baltimore, USA. .
Archives of internal medicine (Impact Factor: 17.33). 09/2008; 168(16):1791-7. DOI: 10.1001/archinte.168.16.1791
Source: PubMed


Common FTO (fat mass and obesity associated) gene variants have recently been associated with body mass index (BMI) and obesity in several large studies. The role of lifestyle factors (such as physical activity) in those with an underlying FTO genetic predisposition is unknown.
To determine if FTO variants are associated with BMI in Old Order Amish (OOA) individuals, and to further determine whether the detrimental associations of FTO gene variants can be lessened by increased physical activity, a total of 704 healthy OOA adults were selected from the Heredity and Phenotype Intervention (HAPI) Heart Study, an investigation of gene x environment interactions in cardiovascular disease, for whom objective quantified physical activity measurements were available and for whom 92 single-nucleotide polymorphisms (SNPs) in FTO were genotyped.
Twenty-six FTO SNPs were associated with BMI (P = .04 to <.001), including rs1477196 (P < .001) and rs1861868 (P < .001), 2 SNPs in moderate linkage disequilibrium in the OOA (D' = 0.82; r(2) = 0.36). Stratified analyses of rs1861868 revealed its association with BMI to be restricted entirely to those subjects with low sex- and age-adjusted physical activity scores (P < .001); in contrast, the SNP had no effect on those with above-average physical activity scores (P = .29), with the genotype x physical activity interaction achieving statistical significance (P = .01). Similar evidence for interaction was also obtained for rs1477196.
Our results strongly suggest that the increased risk of obesity owing to genetic susceptibility by FTO variants can be blunted through physical activity. These findings emphasize the important role of physical activity in public health efforts to combat obesity, particularly in genetically susceptible individuals.

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    • "Several recent studies suggested that physical activity (PA) may attenuate the influence of genetic factors on development of obesity. The most extensively analyzed example of a gene interaction with PA in obesity is for the FTO locus, with various studies concluding in general that physical inactivity accentuates the influence of FTO variants on obesity-related traits (Andreasen et al., 2008; Rampersaud et al., 2008; Ruiz et al., 2010; Xi et al., 2011). However, this gene versus PA interaction in obesity has not yet been assessed in a young adult population. "
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    • "For example, common variants in the FTO obesity gene are associated with increased BMI in populations of sedentary Caucasians. However, the association is either blunted or absent in physically active groups (Rampersaud et al. 2008; Ahmad et al. 2013). There is hope that whole genome sequencing of large numbers of humans will provide more insight into genotype–phenotype relationships for common diseases, but skepticism about what additional insights are possible is understandable given that so little has come from genome-wide association studies. "
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    ABSTRACT: Ideas about personalized medicine are underpinned in part by evolutionary biology's Modern Synthesis. In this essay we link personalized medicine to the efforts of the early statistical investigators who quantified the heritability of human phenotype and then attempted to reconcile their observations with Mendelian genetics. As information about the heritability of common diseases was obtained, similar efforts were directed at understanding the genetic basis of disease phenotypes. These ideas were part of the rationale driving the Human Genome Project and subsequently the personalized medicine movement. In this context, we discuss: (1) the current state of the genotype–phenotype relationship in humans, (2) the common-disease–common-variant hypothesis, (3) the current ability of ‘omic’ information to inform clinical decision making, (4) emerging ideas about the therapeutic insight available from rare genetic variants, and (5) the social and behavioural barriers to the wider potential success of personalized medicine. There are significant gaps in knowledge as well as conceptual, intellectual, and philosophical limitations in each of these five areas. We then provide specific recommendations to mitigate these limitations and close by asking if it is time for the biomedical research community to ‘stop chasing Mendel?’
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    • "Indeed, the contribution of behavioral and environmental factors directly and indirectly by influencing genetic contributions on body weight across phases of adulthood are valid scientific questions in understanding changes to heritability of body weight over the life course. For example, a few studies have found that the association between FTO and BMI varies according to physical activity levels (23,24) and dietary intake (25,26). "
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