FTO association and interaction with time spent sitting

BACKGROUND/OBJECTIVES: Multiple studies have revealed an interaction between a variant in the FTO gene and self-reported physical activity on body-mass index (BMI). Physical inactivity, such as time spent sitting (TSS) has recently gained attention as an important risk factor for obesity and related diseases. It is possible that FTO interacts with TSS to affect BMI, and/or that FTO's putative effect on BMI is mediated through TSS. SUBJECTS/METHODS: We tested these hypotheses in two cohorts of the Framingham Heart Study (FHS) (Offspring: n=3,430, and 3(rd) Generation: n=3,888), and attempted to replicate our results in the Women's Health Initiative (WHI) (n= 4,756). Specifically, we examined whether an association exists between FTO and self-reported TSS, and whether an interaction exists between FTO and TSS on BMI, while adjusting for several important covariates such as physical activity. RESULTS: In FHS, we find a significant positive association between the BMI-increasing FTO allele and TSS. We find a similar trend in WHI. Mediation analyses suggest that the effect of FTO on BMI is mediated through TSS. In FHS, we find a significant interaction of FTO and TSS on BMI, whereby the association of TSS with BMI is greatest among those with more FTO risk alleles. In WHI, we also find a significant interaction, although the direction is opposite to that in FHS. In a meta-analysis of the two datasets, there is no net interaction of FTO with TSS on BMI. CONCLUSIONS: Our study suggests that FTO exerts its effect on BMI, at least partly, through energy expenditure mechanisms such as TSS. Further research into the intersection of genetics, sedentary behavior, and obesity-related outcomes is warranted.