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Renoprotective effe...
Renoprotective effects of genetically proxied fibroblast growth factor 21 : Mendelian randomization, proteome-wide and metabolome-wide association study
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- Giontella, Alice (författare)
- Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups
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- Zagkos, Loukas (författare)
- Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.,Imperial College London
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- Geybels, Milan (författare)
- Novo Nord, Data Sci, Soborg, Denmark.,Novo Nordisk A/S
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- Larsson, Susanna C. (författare)
- Uppsala University,Karolinska Institute,Karolinska Institutet,Uppsala universitet,Medicinsk epidemiologi,Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.
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- Tzoulaki, Ioanna (författare)
- Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Acad Athens, Biomed Res Fdn, Div Syst Biol, Athens, Greece.,Academy of Athens,Imperial College London
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- Mantzoros, Christos S. (författare)
- Harvard Med Sch, Boston VA Healthcare Syst, Dept Med, Boston, MA USA.;Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA.,Harvard Medical School
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- Andersen, Birgitte (författare)
- Novo Nord, Global Drug Dev, Copenhagen, Denmark.,Novo Nordisk A/S
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- Gill, Dipender (författare)
- Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Novo Nord, Chief Sci Advisor Off, Res & Early Dev, Copenhagen, Denmark.,Novo Nordisk A/S,Imperial College London
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- Cronje, Helene T. (författare)
- Univ Copenhagen, Dept Publ Hlth, Sect Epidemiol, Copenhagen, Denmark.;Univ Copenhagen, Dept Publ Hlth, Sect Epidemiol, Oster Farimagsgade 5, DK-1353 Copenhagen, Denmark.,University of Copenhagen
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(creator_code:org_t)
- Elsevier BV, 2023
- 2023
- Engelska.
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Ingår i: Metabolism. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 145
- Relaterad länk:
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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 x 10(-4)), higher urinary sodium excretion (p = 5.1 x 10(-11)), and lower urine albumin-creatinine ratio (p = 3.6 x 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 x 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 x 10(- 07)) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 x 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
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Nyckelord
- Chronic kidney disease
- Fibroblast growth factor 21
- Mendelian randomization
- Proteomics
- Metabolomics
- Chronic kidney disease
- Fibroblast growth factor 21
- Mendelian randomization
- Metabolomics
- Proteomics
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- ref (ämneskategori)
- art (ämneskategori)
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