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Common Variation in the FTO Gene Alters Diabetes-Related Metabolic Traits to the Extent Expected Given Its Effect on BMI

¹ Peninsula Medical School, Exeter, U.K
² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
³ MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Bristol, U.K
⁴ Department of Social Medicine, Bristol University, Bristol, U.K
⁵ National Public Health Institute and University of Oulu, Oulu, Finland
⁶ London School of Hygiene and Tropical Medicine, London, U.K
⁷ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
⁸ National Institute on Aging, National Institutes of Health, Bethesda, Maryland
⁹ II University of Naples, Naples, Italy
¹⁰ Ninewells Hospital and Medical School, University of Dundee, Nethergate, Dundee, Scotland, U.K
¹¹ Department of Epidemiology and Public Health, Imperial College, London, U.K

Corresponding author: Prof. Timothy M. Frayling, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Rd., Exeter, EX1 2LU, U.K. E-mail: tim.frayling{at}pms.ac.uk

Abbreviations: ALT, alanine aminotransferase; BWHHS, British Women's Heart and Health Study; EFSOCH, Exeter Family Study of Childhood Health; GGT, -glutamyl-transferase; NCEP, National Cholesterol Education Program; NFBC1966, Northern Finland Birth Cohort of 1966; NIA, National Institute on Aging; SNP, single nucleotide polymorphism; UKT2D GCC, U.K. Type 2 Diabetes Genetics Consortium Collection

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.

RESEARCH DESIGN AND 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, -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.

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