Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI.
OBJECTIVE
Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.


METHODS
We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.


RESULTS
Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% CI 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.048]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)).


CONCLUSIONS
FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of >12,000 individuals were needed to detect associations at P < 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.
Freathy
Rachel M
RM
Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Rd., Exeter, EX1 2LU, UK.
Timpson
Nicholas J
NJ
Lawlor
Debbie A
DA
Pouta
Anneli
A
Ben-Shlomo
Yoav
Y
Ruokonen
Aimo
A
Ebrahim
Shah
S
Shields
Beverley
B
Zeggini
Eleftheria
E
Weedon
Michael N
MN
Lindgren
Cecilia M
CM
Lango
Hana
H
Melzer
David
D
Ferrucci
Luigi
L
Paolisso
Giuseppe
G
Neville
Matthew J
MJ
Karpe
Fredrik
F
Palmer
Colin N A
CN
Morris
Andrew D
AD
Elliott
Paul
P
Jarvelin
Marjo-Riitta
MR
Smith
George Davey
GD
McCarthy
Mark I
MI
Hattersley
Andrew T
AT
Frayling
Timothy M
TM
D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005060:Europe; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D015201:Meta-Analysis as Topic; D009765:Obesity / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012016:Reference Values; D044465:White People / Q000235:genetics
D001786:Blood Glucose; D007328:Insulin; D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human