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Renoprotective effects of genetically proxied fibroblast growth factor 21 : Mendelian randomization, proteome-wide and metabolome-wide association study

Giontella, Alice LU orcid ; Zagkos, Loukas ; Geybels, Milan ; Larsson, Susanna C. ; Tzoulaki, Ioanna ; Mantzoros, Christos S. ; Andersen, Birgitte ; Gill, Dipender and Cronjé, Héléne T. (2023) In Metabolism: Clinical and Experimental 145.
Abstract

Background: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD). Methods: We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as... (More)

Background: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD). Methods: We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites). Results: We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10−4), higher urinary sodium excretion (p = 5.1 × 10−11), and lower urine albumin-creatinine ratio (p = 3.6 × 10−5). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94–0.98; p = 3.2 × 10−4). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 × 10−07) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 × 10−24) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction. Conclusion: This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to triangulate these findings, towards possible clinical development of FGF21 towards the treatment and prevention of kidney disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Chronic kidney disease, Fibroblast growth factor 21, Mendelian randomization, Metabolomics, Proteomics
in
Metabolism: Clinical and Experimental
volume
145
article number
155616
publisher
Elsevier
external identifiers
  • scopus:85161679478
  • pmid:37302695
ISSN
0026-0495
DOI
10.1016/j.metabol.2023.155616
language
English
LU publication?
yes
id
f147a8f4-f005-497c-a782-06ec2421b482
date added to LUP
2023-09-11 15:13:42
date last changed
2024-02-20 01:01:58
@article{f147a8f4-f005-497c-a782-06ec2421b482,
  abstract     = {{<p>Background: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD). Methods: We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites). Results: We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10<sup>−4</sup>), higher urinary sodium excretion (p = 5.1 × 10<sup>−11</sup>), and lower urine albumin-creatinine ratio (p = 3.6 × 10<sup>−5</sup>). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94–0.98; p = 3.2 × 10<sup>−4</sup>). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p &lt; 1.0 × 10<sup>−07</sup>) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p &lt; 6.5 × 10<sup>−24</sup>) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction. Conclusion: This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to triangulate these findings, towards possible clinical development of FGF21 towards the treatment and prevention of kidney disease.</p>}},
  author       = {{Giontella, Alice and Zagkos, Loukas and Geybels, Milan and Larsson, Susanna C. and Tzoulaki, Ioanna and Mantzoros, Christos S. and Andersen, Birgitte and Gill, Dipender and Cronjé, Héléne T.}},
  issn         = {{0026-0495}},
  keywords     = {{Chronic kidney disease; Fibroblast growth factor 21; Mendelian randomization; Metabolomics; Proteomics}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Metabolism: Clinical and Experimental}},
  title        = {{Renoprotective effects of genetically proxied fibroblast growth factor 21 : Mendelian randomization, proteome-wide and metabolome-wide association study}},
  url          = {{http://dx.doi.org/10.1016/j.metabol.2023.155616}},
  doi          = {{10.1016/j.metabol.2023.155616}},
  volume       = {{145}},
  year         = {{2023}},
}