A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure.
Frayling TM., Beaumont RN., Jones SE., Yaghootkar H., Tuke MA., Ruth KS., Casanova F., West B., Locke J., Sharp S., Ji Y., Thompson W., Harrison J., Etheridge AS., Gallins PJ., Jima D., Wright F., Zhou Y., Innocenti F., Lindgren CM., Grarup N., Murray A., Freathy RM., Weedon MN., Tyrrell J., Wood AR.
Fibroblast 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.