Introduction
Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that is
expressed in the liver, pancreas, skeletal muscle, adipocytes and
brain.1 The effects of FGF21 signalling include
altering of lipid metabolism and macronutrient
preference.1, 2 Increased circulating FGF21 levels
decrease the consumption of sweets and alcohol, but increase dietary
protein intake.2 In rodents and non-human primates,
increased FGF21 signalling has beneficial effects on cardiometabolic
outcomes, such as reduction in fat mass and alleviation of
hyperglycaemia, insulin resistance, dyslipidaemia, and cardiovascular
diseases.3 Furthermore, FGF21 has also been implicated
in protecting against Alzheimer’s disease,4 as well as
improving lifespan.5 However, studies investigating
the effect of FGF21 signalling on these clinical outcomes in humans have
been inconclusive.3, 6 To prioritise the design of
future clinical trials pharmacologically targeting
FGF21,7 we aimed to leverage human genetic data within
the Mendelian randomization paradigm to investigate the effects of
higher genetically proxied circulating FGF21 levels on cardiometabolic
outcomes, Alzheimer’s disease and lifespan.8