Dietary Intake, FTO Genetic Variants, and Adiposity

A Combined Analysis of Over 16,000 Children and Adolescents

Qibin Qi; Mary K. Downer; Tuomas O. Kilpeläinen; H. Rob Taal; Sheila J. Barton; Ioanna Ntalla; Marie Standl; Vesna Boraska; Ville Huikari; Jessica C. Kiefte-de Jong; Antje Körner; Timo A. Lakka; Gaifen Liu; Jessica Magnusson; Masayuki Okuda; Olli Raitakari; Rebecca Richmond; Robert A. Scott; Mark E.S. Bailey; Kathrin Scheuermann; John W. Holloway; Hazel Inskip; Carmen R. Isasi; Yasmin Mossavar-Rahmani; Vincent W.V. Jaddoe; Jaana Laitinen; Virpi Lindi; Erik Melén; Yannis Pitsiladis; Niina Pitkänen; Harold Snieder; Joachim Heinrich; Nicholas J. Timpson; Tao Wang; Hinoda Yuji; Eleftheria Zeggini; George V. Dedoussis; Robert C. Kaplan; Judith Wylie-Rosett; Ruth J.F. Loos; Frank B. Hu; Lu Qi


Diabetes. 2015;64(7):2467-2476. 

In This Article

Abstract and Introduction


The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1–18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 × 10−4), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 × 10−4): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 × 10−10) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents.


Common single nucleotide polymorphisms (SNPs) located in the first intron of the gene associated with fat mass and obesity (FTO) are the first adiposity/BMI-associated variants identified through genome-wide association studies (GWASs),[1–3] and to date this remains the locus with the largest influence on BMI in adults, as well as in children and adolescents.[4] The mechanism by which FTO variants influence adiposity is unclear. Previous animal studies have suggested a role of Fto in regulating energy homeostasis, but it is unknown whether it influences energy intake[5,6] or energy expenditure.[7,8] In addition, it is not clear which gene's function is affected by the functional variants at this locus: FTO itself or another gene located downstream or upstream of FTO, such as IRX3[9] andRPGRIP1L.[10]

In many human studies,[11–20] the BMI-increasing allele of FTO variants has been reported to be associated with increased food intake, total energy intake, fat or protein intake, suggesting that diet mediates the association with BMI. However, these associations have not been replicated in a number of other studies.[21–35] In addition, there is an increasing interest in examining whether lifestyle factors influence the associations between FTO variants and adiposity. While there is evidence that physical activity reduces the effect of FTO on BMI, at least in adults,[36] the few studies[12,20,26,32,34,35,37,38] that have investigated interaction with dietary factors in relation to BMI/obesity have generated conflicting results regarding potential interactions. Our recent large-scale meta-analysis[39] indicated that FTO variants were associated with protein intake in adults and that under-reporting of dietary intake in obese participants might be a major issue in the analysis. Studies in children are of particular interest in this regard, since this population is less biased by comorbidities, and their treatment and exposure to environmental contributors is shorter.

The relatively small sample size of individual studies, the modest genetic effect size, and the inevitable measurement errors might be major reasons for these inconsistent observations. Thus, studies with larger sample sizes are needed to clarify interrelations among FTO variants, dietary intake, and adiposity. Herein we report the results of a combined analysis of 16,094 children and adolescents from 14 studies to examine the following: 1) whether the FTO rs9939609 variant (or a proxy SNP) is associated with dietary intake of total energy and macronutrients (protein, carbohydrate, and fat); and 2) whether dietary intake influences the association between the FTO variant and BMI.