Low Physical Activity Accentuates the Effect of the FTO rs9939609 Polymorphism on Body Fat Accumulation

Abstract

OBJECTIVE-Three independent studies have shown that variation in the fat mass and obesity-associated (FTO) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined. RESEARCH DESIGN AND METHODS-The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups.RESULTS-In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of rs9939609 associated with type 2 diabetes (odds ratio 1.13 [95% CI 1.06 -1.20], P ϭ 9 ϫ 10 Ϫ5 ). This association was abolished when adjusting for BMI (1.06 [0.97-1.16], P ϭ 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13-1.24], P ϭ 1 ϫ 10 Ϫ12 ) and obesity (1.27 [1.20 -1.34], P ϭ 2 ϫ 10 Ϫ16 ). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity (P ϭ 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 Ϯ 0.3 kg/m 2 increase in BMI compared with homozygous T-allele carriers.CONCLUSIONS-We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore, low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation. Diabetes 57:95-101, 2008 W orldwide incidence of obesity has increased dramatically and is today one of the leading causes of lifestyle-related disorders such as type 2 diabetes and premature cardiovascular disease. Association between common forms of obesity and genes such as GAD2 (1), ENPP1 (2), and INSIG2 (3) have been reported but difficult to validate (4 -6). Recently, variation in the fat mass and obesity-associated (FTO) gene was reported to associate with type 2 diabetes and increased fat mass. As a part of the Wellcome Trust Case Control Consortium genome-wide association study, which included 1,924 U.K. type 2 diabetic patients and 2,938 U.K. normoglycemic control subjects, an FTO variant (rs9939609) was found to associate with type 2 diabetes; however, this association abolished following adjustment for BMI (7). Subsequently, an association with overweight and obesity was demonstrated in seven population-based study samples comprising a total of 19,424 white European adults and two birth cohorts including 10,172 white European children. Moreover, evidence was presented that the increase in BMI resulted from an overall increase in body fat, evaluated by waist circumference and fat mass estimates, including skinfold measures (7).In another independent study, the effect of 48 neutral single-nucleotide polymorphisms (SNPs) on obesity was tested in 2,900 obese and 5,100 control subjects of European ancestry, and the FTO rs1121980 polymorphism, also ...

The genetic and environmental influences on childhood obesity: a systematic review of twin and adoption studies

“…There is also evidence suggesting a modifying effect of physical activity on specific genes; a Danish study found that the rs9939609 polymorphism of the FTO gene is associated with greater BMI in sedentary persons than in physically active persons. 62 Similar results have also been reported in an Amish population. 63 The studies were cross-sectional in design and the findings therefore need confirmation in prospective studies, excluding an effect of development of obesity on physical activity.…”

Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents

“…Thus, this FTO gene variant associates with other phenotypes when compared with previously studied FTO variants where the associations are almost exclusively mediated by differences in BMI. 6,8,9 The FTO gene encodes a probable 2-oxoglutarate-dependent nucleic acid demethylase 19 and is expressed in multiple peripheral and central tissues, 3,20 which is characteristic for a gene that may display a pleiotropic character influencing several systems simultaneously. This suggests that FTO and polymorphism, such as c.896 þ 223A4G and rs9939609, that are not in linkage disequilibrium with each other may have different molecular effects on metabolic conditions and phenotypes.…”

“…[3][4][5] Increased BMI levels and risk of obesity for FTO variants have been replicated in several cohorts consisting of adults 5 as well as adults and children. 3,4,6,7 Associations between FTO variants and metabolic traits such as fasting insulin, glucose, cholesterol and triglycerides have also been found. These associations were, however, abolished when adjusting for BMI.…”

“…These associations were, however, abolished when adjusting for BMI. 6,8,9 Although a large number of polymorphisms in FTO have been shown to be associated with obesity, none has been thoroughly investigated in terms of detailed phenotypic characteristic of metabolic conditions to elucidate the causative mechanisms or variants. The studies performed so far have, in addition, all been focused on known common variants.…”

Influence of physical activity on the association between the FTO variant rs9939609 and adiposity in young adults

“…The most extensively studied example of a gene interaction with physical activity in obesity is for the FTO locus, concluding in general that physical inactivity accentuates the association of FTO variants with obesity-related traits (Andreasen et al, 2008;Rampersaud et al, 2008;Lee et al, 2010;Ruiz et al, 2010;Xi et al, 2011). However, this gene versus physical activity interaction in obesity was not yet assessed in a young adult population.…”