Genetic evidence for repurposing GLP‐1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti‐inflammatory pathways beyond glycaemic control
Authors' conclusion
This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.
Study context
- Population
- Large-scale Genome - Wide Association Study (GWAS) data (MRC IEU OpenGWAS, FinnGen, GWAS Catalogue, cohort-specific studies); European ancestry
- Comparison
- Genetically predicted GLP-1R activation
- Outcome
- CKD, eGFR and CKD subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome, chronic glomerulonephritis)
Methodological detailsgenetic proxies for GLP-1R activation, positive controls (HbA1c, blood glucose, T2DM, diabetic nephropathy (DN)), mediation Mendelian randomisation (MR), sensitivity analyses
- Genetic proxies for GLP-1R activation
- Positive controls (HbA1c, blood glucose, T2DM, DN)
- Mediation MR
- Sensitivity analyses
Main finding
As reported in the abstract
Chronic kidney disease (CKD) risk, OR
0.83
p = 9.22E-9
Immunoglobulin A nephropathy (IgAN) risk, OR
0.70
p = 2.11E-3
Kidney function preservation (estimated glomerular filtration rate (eGFR)), β
0.01
p = 9.11E-3
Further findings
Positive controls
- Reduced HbA1c
- P = 4.93E-15
- Reduced blood glucose
- P = 9.73E-5
- Decreased T2DM risk
- P = 2.45E-4
- Decreased DN risk
- P = 6.35E-4
Mediation: proportion of effect mediated
- FGF23 suppression, eGFR
- 26.57%
- FGF23 suppression, CKD
- 13.50%
- Body mass index (BMI), CKD
- 2.08%
- BMI, eGFR
- 5.51%
- HDL, CKD
- 0.79%
- HDL, eGFR
- 2.34%
- HbA1c, eGFR
- 8.25%
- Only BMI mediated the effect on IgAN
Sensitivity analyses
- Minimal pleiotropy
Original publication
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