Genetically proxied glucagon-like peptide-1 receptor agonist is associated with risk of tubulo-interstitial nephritis: A network Mendelian randomization study

Glucagon-like peptide-1 receptor (GLP1R) agonists (GLP1RAs) are widely used in type 2 diabetes mellitus (T2DM) management due to their glycemic and cardiorenal benefits, yet emerging evidence suggests potential renal adverse effects, particularly tubulo-interstitial nephritis (TIN). We conducted a 2-sample Mendelian randomization (MR) analysis to investigate causal relationships between GLP1RA use and TIN risks. Genetic proxies for GLP1RA effects were derived from cis-eQTLs for GLP1R. Proteome-wide MR and mediation analyses with UK Biobank Pharma Proteomics Project data were also used to identify mediating plasma proteins and biological pathways. MR analyses showed a significant causal link between GLP1RA use and chronic tubulo-interstitial nephritis (CTIN; OR = 2.32, 95% CI = 1.39-3.85, P = .001), with no significant association for acute tubulo-interstitial nephritis (ATIN; OR = 0.93, 95% CI = 0.83-1.04, P = .216). Colocalization analysis strongly supported the MR findings, showing a high posterior probability of shared genetic variants between GLP1R expression and CTIN (PP.H4 = 0.99). Mediation analysis identified 4 plasma proteins (HYAL1, NMNAT1, IL12RB2, and DPP6) as partial mediators of the effect. Genetic evidence from this study indicated an association between GLP1R agonists and higher risk of chronic tubulo-interstitial nephritis. Potential risks need to be evaluated when prescribing GLP1RAs in in clinical practice.