Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation.
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.


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 = 9 x 10(-5)). This association was abolished when adjusting for BMI (1.06 [0.97-1.16], P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13-1.24], P = 1 x 10(-12)) and obesity (1.27 [1.20-1.34], P = 2 x 10(-16)). 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 = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 +/- 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.
Andreasen
Camilla H
CH
Steno Diabetes Center, Niels Steensens Vej 1, NLC2.13, DK-2820 Gentofte, Denmark. cila@novonordisk.com
Stender-Petersen
Kirstine L
KL
Mogensen
Mette S
MS
Torekov
Signe S
SS
Wegner
Lise
L
Andersen
Gitte
G
Nielsen
Arne L
AL
Albrechtsen
Anders
A
Borch-Johnsen
Knut
K
Rasmussen
Signe S
SS
Clausen
Jesper O
JO
Sandbaek
Annelli
A
Lauritzen
Torsten
T
Hansen
Lars
L
Jørgensen
Torben
T
Pedersen
Oluf
O
Hansen
Torben
T
D000273:Adipose Tissue / Q000033:anatomy & histology*; D000328:Adult; D015992:Body Mass Index; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009043:Motor Activity; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D016017:Odds Ratio; D007652:Oxo-Acid-Lyases / Q000235:genetics*; D011110:Polymorphism, Genetic; D012016:Reference Values
D007652:Oxo-Acid-Lyases