Lifestyle interaction with fat mass and obesity-associated (FTO) genotype and risk of obesity in apparently healthy U.S. women

Abstract

Objective: Variation in the fat mass and obesity-associated (FTO) gene is associated with obesity. The extent to which separate and combined effects of physical activity and caloric intake modify this association remains unclear.

Research design and methods: FTO polymorphism rs8050136 was measured, and physical activity, caloric intake, and anthropometrics were self-reported in 21,675 apparently healthy Caucasian women.

Results: The effect of the risk allele (A) on BMI was larger among inactive or higher intake women, with additive effects of inactivity and high intake on the associated genetic risk. Specifically, each A allele was associated with mean BMI difference of +0.73 (SE 0.08) kg/m(2) among inactive women (≤ median, 8.8 MET-hours/week), compared with +0.31 (0.06) kg/m(2), P < 0.0001, among active women (>8.8 MET-hours/week). Similarly, each A allele was associated with mean BMI difference of +0.65 (0.07) among high intake women (>median, 1,679 kcals/day), compared with +0.38 (0.07) kg/m(2), P = 0.005, among low intake women (≤ 1,679 kcals/day). Among inactive/high intake women, each A allele was associated with mean BMI difference of +0.97 (0.11) kg/m(2) vs. +0.22 (0.08) kg/m(2) among inactive/low intake women, P < 0.0001. Among inactive/high intake women, each A allele carried increased risk of obesity (odds ratio 1.39, 95% CI 1.27-1.52) and diabetes (odds ratio 1.36, 95% CI 1.07-1.73).

Conclusions: In this study, lifestyle factors modified the genetic risk of FTO on obesity phenotypes, particularly among women who were both inactive and had high intake. Healthier lifestyle patterns blunted but did not completely eliminate the associated genetic risk.

Figure 1

The difference in mean BMI per FTO A allele at prespecified percentiles of physical activity and caloric intake, with and without adjustment. The values for MET-hours per week and kilocalories per day represent the following percentile groups: <10%, ≥10–25%, >25–50%, >50–75%, >75–90%, and >90%. The bars represent means and SE. For physical activity, the P values within each percentile category for the association of the A allele with mean BMI (starting with <10% and ending with >90%) were <0.0001, <0.0001, <0.0001, 0.0001, 0.02, and 0.01, respectively. For caloric intake, the respective P values were 0.03, 0.002, <0.0001, <0.0001, <0.0001, and <0.0001. Tests for these interactions were significant (P before adjustment: <0.001 and <0.001; after mutual adjustment: <0.001 and 0.003, for physical activity and caloric intake, respectively).