Genetic Evidence Supporting Fibroblast Growth Factor 21 Signalling as a Pharmacological Target for Cardiometabolic Outcomes and Alzheimer's Disease.

Susanna C. Larsson,Dipender Gill

doi:10.3390/nu13051504

Abstract

Fibroblast growth factor 21 (FGF21) is a human metabolic hormone whose effects include modification of macronutrient preference and energy homeostasis. In animal models, FGF21 has been shown to have beneficial effects on cardiometabolic outcomes, Alzheimer’s disease risk and lifespan. In this study, the single-nucleotide polymorphism rs838133 in the FGF21 gene region was leveraged to investigate the potential clinical effects of targeting FGF21. The FGF21 G allele was associated with lower intakes of total sugars and alcohol, and higher intakes of protein and fat as well as favourable with lipid levels, blood pressure traits, waist-to-hip ratio, systemic inflammation, cardiovascular outcomes, Alzheimer’s disease risk and lifespan. These findings may be used to anticipate the effects of pharmacologically increasing FGF21 signalling.

Highlights

Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that is expressed in the liver [1]
We aimed to leverage human genetic data within the Mendelian randomization paradigm to investigate the associations of a common allele in the FGF21 gene with cardiometabolic outcomes, Alzheimer’s disease and lifespan [11]
The G allele of rs838133 in the FGF21 gene region was associated with lower intakes of total sugars and alcohol, and higher intakes of protein and fat (Figure 1), consistent with the expected effect of an increase in FGF21 concentration

Summary

Introduction

Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that is expressed in the liver [1]. In rodents and non-human primates, FGF21 treatment has beneficial effects on cardiometabolic outcomes, such as reduction in fat mass and alleviation of hyperglycaemia, insulin resistance, dyslipidaemia, and cardiovascular diseases [7]. FGF21 has been implicated in protecting against Alzheimer’s disease [8], as well as improving lifespan [9]. Studies investigating the association between circulating FGF21 and these clinical outcomes in humans have been inconclusive [7,10]. To investigate this further, we aimed to leverage human genetic data within the Mendelian randomization paradigm to investigate the associations of a common allele in the FGF21 gene with cardiometabolic outcomes, Alzheimer’s disease and lifespan [11]

Objectives

Methods

Results

Conclusion