A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordFibroblast growth factor 21 (FGF21) is a hormone that has insulin-sensitizing properties. Some trials of FGF21 analogs show weight loss and lipid-lowering effects. Recent studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed, but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study, aiming to use the human allele to inform potential adverse and beneficial effects of targeting FGF21. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with higher blood pressure and waist-hip ratio, despite an association with lower total body-fat percentage, than it is with BMI or type 2 diabetes. These human phenotypes of variation in the FGF21 gene will inform research into FGF21’s mechanisms and therapeutic potential.A.R.W. and T.M.F. are supported by the European Research Council (grant 323195:GLUCOSEGENES-FP7-IDEAS-ERC). R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant 104150/Z/14/Z). H.Y. is an RD Lawrence Fellow, funded by Diabetes UK. R.N.B. is funded by the Wellcome Trust and Royal Society grant 104150/Z/14/Z. J.T. is funded by the European Regional Development Fund (ERDF) and a Diabetes Research and Wellness Foundation fellowship. S.E.J. is funded by the Medical Research Council (grant MR/M005070/1). M.A.T., M.N.W., and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). C.M.L. is supported by the Li Ka Shing Foundation, by the National Institute for Health Research (NIHR) Biomedical Research Centre (Oxford), by Widenlife, and by the NIH (CRR00070 CR00.01). The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://cbmr.ku.dk). This research has been conducted using the UK Biobank resource. This work was carried out under UK Biobank project numbers 9072 and 9055