Physical activity and the association of common FTO gene variants with body mass index and obesity

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1

Linkage disequilibrium (LD) structure and FTO single-nucleotide polymorphism (SNP) associations with body mass index (BMI). A, For each SNP surrounding rs9939609, we show –log10 (P value) for the additive model in the Old Order Amish (OOA). B, The LD (r ²) of FTO in OOA white subjects. C, The LD (r ²) of FTO in the HapMap (http://www.hapmap.org) genotype of white individuals. The association of rs9939609 with BMI was first reported in European white individuals and subsequently in French white individuals; rs9930506 was the SNP most highly associated with BMI in a Sardinian population; rs8050136 was associated with type 2 diabetes mellitus (T2DM) in European white subjects.^- Zeggini et al later found that the association disappeared after adjustment for BMI. In an independent sample of 419 OOA subjects (of whom 124 had T2DM), rs8050136 was associated with T2DM (P = .007), and this association was abolished after adjustment for BMI (P = .53) (data not shown). rs9939609, rs9930506, and rs8050136 all reside in a cluster of SNPs in high LD in HapMap genotypes of white individuals. Black squares indicate r ²>0.80; gray squares, 0.10 ≥r²≤0.80; white squares, r²<0.10. kb Indicates kilobases.

Figure 2

Mean body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, in high and low physical activity groups according to FTO single-nucleotide polymorphism genotypes for rs1861868 (A) and rs1477196 (B). High activity was defined as age-, age-, and sex-specific residuals greater than 0, and low activity was defined by residuals less than 0. Interaction P values: rs1861868, P = .01; rs1477196, P = .004.

Figure 3

Predicted body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, as a function of residualized age- and sex-specific ln-transformed physical activity accelerometer counts according to FTO rs1861868 genotypes. On the left side of the plot (low physical activity), BMI levels are strikingly dissimilar between rs1861868 genotypes. In contrast, on the right side of the plot, similar BMI levels can be seen across genotypes, particularly in subjects with very high levels of physical activity.