Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene.
BACKGROUND
Intronic variation in the FTO (fat mass and obesity-associated) gene has been unequivocally associated with increased body mass index (BMI; in kg/m(2)) and the risk of obesity in populations of different ethnicity.


OBJECTIVE
We examined whether this robust genetic predisposition to obesity can be attenuated by being more physically active.


METHODS
The FTO variant rs1121980 was genotyped in 20,374 participants (39-79 y of age) from the European Prospective Investigation into Cancer and Nutrition-Norfolk Study, an ethnically homogeneous population-based cohort. Physical activity (PA) was assessed with a validated self-reported questionnaire. The interaction between rs1121980 and PA on BMI and waist circumference (WC) was examined by including the interaction term in mixed-effect models.


RESULTS
We confirmed that the risk (T) allele of rs1121980 was significantly associated with BMI (0.31-unit increase per allele; P < 0.001) and WC (0.77-cm increase per allele; P < 0.001). The PA level attenuated the effect of rs1121980 on BMI and WC; ie, whereas in active individuals the risk allele increased BMI by 0.25 per allele, the increase in BMI was significantly (P for interaction = 0.004) more pronounced (76%) in inactive individuals (0.44 per risk allele). We observed similar effects for WC (P for interaction = 0.02): the risk allele increased WC by 1.04 cm per allele in inactive individuals but by only 0.64 cm in active individuals.


CONCLUSIONS
Our results showed that PA attenuates the effect of the FTO rs1121980 genotype on BMI and WC. This observation has important public health implications because we showed that a genetic susceptibility to obesity induced by FTO variation can be overcome, at least in part, by adopting a physically active lifestyle.
Vimaleswaran
Karani S
KS
MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom.
Li
Shengxu
S
Zhao
Jing Hua
JH
Luan
Jian'an
J
Bingham
Sheila A
SA
Khaw
Kay-Tee
KT
Ekelund
Ulf
U
Wareham
Nicholas J
NJ
Loos
Ruth J F
RJ
D000328:Adult; D000368:Aged; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D015331:Cohort Studies; D015444:Exercise / Q000502:physiology*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000208:ethnology / Q000235:genetics* / Q000517:prevention & control; D011506:Proteins / Q000235:genetics*; D055105:Waist Circumference
D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human