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

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.

New developments in the biology of fibroblast growth factors

“…MR analysis of a common variant in FGF21 demonstrated an association with lower intakes of total sugars and alcohol, higher intakes of protein and fat, as well as favorable lipid levels, blood pressure traits, waist‐to‐hip ratio, systemic inflammation, cardiovascular outcomes, Alzheimer's disease risk, and lifespan. These findings anticipate the effects of pharmacologically increasing FGF21 signaling (Larsson & Gill, 2021).…”

Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH

“…The strongest SNP near the FGF21 locus that was identified in our GWAS is in modest linkage disequilibrium (R 2 ≈ 0.3) with SNPs (rs838133 and rs838145) previously found to associate with relative intake of macronutrients in GWAS analyses [19,20]. The SNP rs838133 has also been reported to be strongly associated with alcohol consumption, fat mass, lipids, liver enzymes (gamma-glutamyl transferase, ALP, and AST), and CRP concentrations [8,54], suggestively associated with major cardiovascular diseases (except for strong association with venous thromboembolism), Alzheimer's disease, and lifespan [54], but not associated with glycemic traits or type 2 diabetes [8,54]. A weak association was found between rs838145 and FGF21 protein concentrations in 377 individuals (P = 0.01) [20].…”