title: Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI.
abstract: 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.
authors.affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Rd., Exeter, EX1 2LU, UK.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: Beverley
authors.initials: B
authors.lastname: Shields
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Hana
authors.initials: H
authors.lastname: Lango
authors.forename: David
authors.initials: D
authors.lastname: Melzer
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paolisso
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Neville
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human