Discussion
FGF21 signalling is being pursued as a pharmacological target in early stage clinical trials.7 Our current study leveraged genetic data to provide insight into the broad metabolic and clinical effects of FGF21 in humans. The results support previously reported associations of genetically proxied circulating FGF21 levels with lipid levels, blood pressure, fat mass, and liver enzymes as well as the lack of association with type 2 diabetes.6 Our present study went further to provide novel evidence that increased FGF21 signalling decreases chronic inflammation measured using C-reactive protein). We also identified a potential beneficial effect of FGF21 on cardiovascular outcomes. Additionally, our results support a beneficial effect of higher circulating FGF21 levels on Alzheimer’s disease and lifespan.
These findings inform on the potential effects of pharmacologically increasing FGF21 levels and signalling. Of note, the genetic variant used to proxy FGF21 levels reflects small, lifelong increases in FGF21 levels, and the results therefore inform on the effects of elevating circulating FGF21 levels and signalling in the long-term. The limitations of this study should also be acknowledged. Critically, it is possible that some of the identified associations may be attributable to genetic confounding, where the genetic variant used to proxy circulating FGF21 also has pleiotropic associations unrelated to FGF21. As summary genetic association data for circulating FGF21 levels were not available, we could not perform colocalization analysis to explore this.10 Furthermore, the outcomes that we studied were determined by the availability of corresponding large-scale genetic association summary data. As such, it was not possible to perform analyses for other relevant traits, such as non-alcoholic steatohepatitis.
In summary, we used a human genetic proxy for higher circulating FGF21 levels to identify evidence for favourable effects of its signalling in humans on a range of cardiometabolic outcomes, Alzheimer’s disease and lifespan. This work should be used to inform the design of further clinical studies.