Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations

Abstract

Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993-2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987-1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991-1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10(-5)) and inversely associated with percentage of calories derived from carbohydrate (βmeta = -0.2796 (standard error, 0.0709); P = 8 × 10(-5)). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)(2)) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m(2), 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake.

Replication of the Association of BDNF and MC4R Variants With Dietary Intake in the Diabetes Prevention Program

“…However, consistent with prior findings [10,14,18], a nominal association between the obesity-associated, minor allele at FTO rs1421085 and greater percentage fat intake (β=0.37, SE=0.08; P =0.0418) was observed in the non-Hispanic White participants only. The minor allele at FLJ35779 rs2112347 was further associated with lower percentage protein intake (β=−0.30, SE=0.09; P =0.0006) in this subsample.…”

“…Consistent with this hypothesis, the FTO single nucleotide polymorphism (SNP) rs9939609 has been shown to predict preferences for and consumption of palatable, calorie dense foods [9,10] and reduced satiety [11], and greater total caloric and fat intake [10]. In a recent GWAS of dietary intake, FTO was associated, albeit inconsistently, with a greater percentage of calories from protein [12,13] and fat [14]. MC4R obesity risk alleles were associated with greater caloric intake and percent fat intake in the Nurses’ Health Study [15] but not in another sample of men and women [16], and obesity risk alleles at SH2B1 were associated with greater total, saturated, and monounsaturated fat intake in Dutch women [17].…”

What Twin Studies Tell Us About Brain Responses to Food Cues

“…For example, in a UK study of 131 4–5 year olds in which EAH intake was assessed at the participants’ homes using a free-access procedure that provided three varieties of (sweet and savory) biscuit snacks to children, those with one or two copies of the A (risk) allele for the FTO polymorphism rs9939609 consumed significantly more biscuits in the absence of hunger compared to children with no risk allele [62]. Supporting this result, other studies have demonstrated high-risk alleles on FTO to be associated with increased energy intake [63–66], increased intake of dietary fat [67, 68] and protein [69], and perceived loss of control over eating [70]. …”

Obesity and FTO: Changing Focus at a Complex Locus

“…Obesity-associated FTO SNPs were found to be associated with increased energy intake (Cecil et al, 2008;Speakman et al, 2008;Timpson et al, 2008), increased intake of dietary fat (Park et al, 2013;Timpson et al, 2008) or protein (Sonestedt et al, 2009), increased appetite and reduced satiety (Wardle et al, 2008(Wardle et al, , 2009, and loss of control over eating (TanofskyKraff et al, 2009). This link with food intake was not seen in every study; for example, a report by Stutzmann et al (2009) failed to find an association of the FTO rs 1421085 C allele with eating behavior traits in a large European cohort of children and adults.…”