Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI

doi:10.2337/db07-1466

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Original Research

Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI

Rachel M Freathy, PhD¹, Nicholas J Timpson, PhD^2,^,3, Debbie A Lawlor, PhD^3,^,4, Anneli Pouta, PhD⁵, Yoav Ben-Shlomo, PhD⁴, Aimo Ruokonen, PhD⁵, Shah Ebrahim, DM⁶, Beverley Shields, PhD¹, Eleftheria Zeggini, PhD², Michael N Weedon, PhD¹, Cecilia M Lindgren, PhD^2,^,7, Hana Lango, MSc¹, David Melzer, PhD¹, Luigi Ferrucci, PhD⁸, Giuseppe Paolisso, MD⁹, Matthew J Neville, DPhil⁷, Fredrik Karpe, PhD⁷, Colin N A Palmer, PhD¹⁰, Andrew D Morris, MD¹⁰, Paul Elliott, PhD¹¹, Marjo-Riitta Jarvelin, PhD^5,^,11, George Davey Smith, DSc^3,^,4, Mark I McCarthy, FMedSci^2,^,7, Andrew T Hattersley, DM¹, and Timothy M Frayling, PhD¹

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

Objective: Common variation in the FTO gene is associated with body massindex (BMI) and type 2 diabetes. Increased BMI is associatedwith diabetes risk factors including raised insulin, glucoseand triglycerides. We aimed to test whether FTO genotype isassociated with variation in these metabolic traits.

Research design and methods: We tested the association between FTO genotype and ten metabolictraits using data from 17,037 white European individuals. Wecompared the observed effect of FTO genotype on each trait tothat expected given the FTO-BMI and BMI-trait associations.

Results: Each copy of the FTO rs9939609 A allele was associated withhigher fasting insulin (0.039SD [95%CI:0.013-0.064]; P=0.003),glucose (0.024SD [0.001-0.048]; P=0.044), and triglycerides(0.028SD [0.003-0.052]; P=0.025), and lower HDL-cholesterol(0.032SD [0.008-0.057]; P=0.009). There was no evidence of theseassociations when adjusting for BMI. Associations with fastingalanine-aminotransferase, gamma-glutamyl-transferase and LDL-cholesterol,HbA1c and systolic and diastolic blood pressure were in theexpected direction but did not reach P<0.05. For all metabolictraits, effect sizes were consistent with those expected forthe per-allele change in BMI. FTO genotype was associated witha higher odds of metabolic syndrome (odds ratio:1.17 [95%CI:1.10-1.25];P=3x10^–6).

Conclusions: FTO genotype is associated with metabolic traits to an extententirely consistent with its effect on BMI. Sample sizes ofgreater than 12,000 individuals were needed to detect associationsat P<0.05. Our findings highlight the importance of usingappropriately-powered studies to assess the effects of a knowndiabetes or obesity variant on secondary traits correlated withthese conditions.

Correspondence: tim.frayling{at}pms.ac.uk

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