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 ...

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Background-Previous studies reveal major differences in the estimated cardiovascular risk in diabetes mellitus, including uncertainty about the risk in young patients. Therefore, large studies of well-defined populations are needed. Methods and Results-All residents in Denmark Ն30 years of age were followed up for 5 years (1997 to 2002) Results for women were 2.48 (95% CI, 2.43 to 2.54) and 2.71 (95% CI, 2.65 to 2.78) (Pϭ0.001), respectively. Risks were similar for both diabetes types. Analyses with adjustments for comorbidity, socioeconomic status, and prophylactic medical treatment showed similar results, and propensity score-based matched-pair analyses supported these findings. Conclusions-Patients requiring glucose-lowering therapy who were Ն30 years of age exhibited a cardiovascular risk comparable to nondiabetics with a prior myocardial infarction, regardless of sex and diabetes type. Therefore, requirement for glucose-lowering therapy should prompt intensive prophylactic treatment for cardiovascular diseases.