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

TLDR

FTO gene variants are known to be associated with body mass index and obesity, yet the influence of lifestyle factors such as physical activity on this genetic risk remains unclear. The study aimed to determine whether FTO variants are linked to BMI in Old Order Amish adults and whether higher physical activity could mitigate these genetic effects. Researchers genotyped 92 FTO SNPs in 704 Amish participants with objectively measured physical activity from the HAPI Heart Study. Twenty‑six FTO SNPs, including rs1477196 and rs1861868, were associated with BMI, but the association appeared only in individuals with low physical activity, while those with higher activity showed no effect, indicating that physical activity can blunt the obesity risk conferred by these variants.

Abstract

<h3>Background</h3> Common<i>FTO</i>(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<i>FTO</i>genetic predisposition is unknown. <h3>Methods</h3> To determine if<i>FTO</i>variants are associated with BMI in Old Order Amish (OOA) individuals, and to further determine whether the detrimental associations of<i>FTO</i>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 × environment interactions in cardiovascular disease, for whom objective quantified physical activity measurements were available and for whom 92 single-nucleotide polymorphisms (SNPs) in<i>FTO</i>were genotyped. <h3>Results</h3> Twenty-six<i>FTO</i>SNPs were associated with BMI (<i>P</i> = .04 to &lt;.001), including rs1477196 (<i>P</i> &lt; .001) and rs1861868 (<i>P</i> &lt; .001), 2 SNPs in moderate linkage disequilibrium in the OOA (<i>D</i>′ = 0.82;<i>r</i>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 (<i>P</i> &lt; .001); in contrast, the SNP had no effect on those with above-average physical activity scores (<i>P</i> = .29), with the genotype × physical activity interaction achieving statistical significance (<i>P</i> = .01). Similar evidence for interaction was also obtained for rs1477196. <h3>Conclusions</h3> Our results strongly suggest that the increased risk of obesity owing to genetic susceptibility by<i>FTO</i>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.