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.