Prospective Analysis of the Association of a Common Variant of FTO (rs9939609) with Adiposity in Children: Results of the IDEFICS Study

Abstract

ObjectivesWe investigated cross-sectionally and longitudinally the relationship between FTO rs9939609 and obesity-related characteristics in the European children of the IDEFICS project and the interaction of this variant with a lifestyle intervention.Population and MethodsA cohort of 16224 children (2–9 years) was recruited into a population-based survey (T0) from eight European countries. A second survey (T1) reassessed the children two years later. A random sample of 4405 children was extracted for genetic studies. 3168 children were re-examined two years later. Half of them underwent a lifestyle intervention program. The FTO rs9939609 was genotyped. Weight, height, waist circumference, triceps and subscapular skinfolds were measured at T0 and T1.ResultsAt T0, the risk A allele of rs9939609 was significantly associated with higher values of body mass index (BMI), waist circumference and skinfolds (age, sex, and country-adjusted p-values: all p<0.001) and with a statistically significant increased risk of overweight/obesity.Over the two year follow-up, no interaction between genotype and intervention was observed. The A allele was associated to a significantly higher increase in all the anthropometric variables examined at T0 independently from the study group (intervention versus control) (p-values: all p<0.002, adjusted for age, sex, country, intervention/control study group, T0 values, and individual time interval between T0 and T1). Over the two-year follow–up, 210 new cases of overweight/obesity occurred. A statistically significant higher incidence of overweight/obesity was associated to the A allele [ORA = 1.95, 95% CI = (1.29; 2.97)].ConclusionsWe confirmed the association between the FTO rs9939609 and body mass and overweight/obesity risk in European children. The main finding of the study is that the A allele carriers present higher increase of body mass and central adiposity over time and higher risk of developing overweight/obesity during growth, independently from intervention measures.

A link between FTO, ghrelin, and impaired brain food-cue responsivity

“…FTO overexpression reduces ghrelin pre-mRNA m 6 A-specific methylation. FTO directly demethylates N 6 -methyladenosine (m 6 A), a naturally occurring adenosine modification in RNA (30) thought to regulate gene expression (31,32).…”

“…In light of our findings that FTO overexpression increased ghrelin mRNA levels in MGN3-1 and HEK293T cells, we next examined whether the ghrelin pre-m-RNA m 6 A methylation status was altered by FTO overexpression by conducting m 6 A-specific methylated RNA immunodepletion studies (32) on total cellular mRNA from MGN3-1 and HEK293T cells. These studies demonstrate that FTO overexpression specifically reduced m 6 A methylation of ghrelin mRNA in both cell lines ( Figure 6, A and B), but not that of RPS14 ( Figure 6, C and D), a non-m 6 A methylated mRNA (32).…”

“…Genome-wide association studies (GWAS) have reliably established that SNPs within the first intron of FTO are robustly associated with increased BMI and adiposity across different ages and populations (2)(3)(4)(5)(6). Subjects homozygous for the "obesity-risk" A allele of FTO rs9939609 have a 1.7-fold increased risk for obesity compared with subjects homozygous for the low-risk T allele (2).…”

“…Two studies combining m 6 A-specific methylated RNA immunoprecipitation with next-generation sequencing have defined human and mouse m 6 A RNA methylomes for specific cell types and suggest that m 6 A methylation of RNA plays a fundamental role in the regulation of gene expression (31,32). In addition, recent cellular studies have implicated a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 (MTORC1) signaling, suggesting that FTO SNPs may influence the ability of cells to sense amino acids (24).…”

“…Next, we undertook a series of studies to explore the mechanistic link between FTO and ghrelin. We measured ghrelin levels in Fto KO mice (25) and examined the effect of FTO overexpression on ghrelin mRNA abundance and m 6 A methylation and total ghrelin and acyl-ghrelin concentrations in both MGN3-1 cells, a ghrelin-producing mouse cell line (40), and in HEK293T human cells. Finally, we analyzed FTO expression, ghrelin mRNA m 6 A methylation, and ghrelin expression in peripheral blood cells from AA and TT subjects.…”