Genetic GLP1R Gene Expression and Kidney Disease Progression: A Mechanistic Proteome-Wide Analysis in the Million Veteran Program

Background: Glucagon-like peptide-1 receptor agonists (GLP1RA) may have nephroprotective properties beyond weight loss and glycemic control. We assessed the effect of genetically proxied GLP1RA on kidney disease progression, while accounting for its effects on obesity and diabetes as well the plasma proteome. Methods: We assembled a national retrospective cohort of Veterans from the Million Veteran Program between 2011 and 2021. A Cox proportional hazards survival analysis assessed the association between genetically proxied GLP1RA and kidney disease progression. A proteome-wide mendelian randomization analysis examined the effect of genetically proxied GLP1RA on changes in plasma protein levels to provide mechanistic insights. The exposure was a genetic risk score for systemic GLP1R gene expression that was calculated for each study participant based on genetic variants associated with GLP1R mRNA levels within the Genotype-Tissue Expression project. The primary composite outcome was the incident 40% decline of estimated glomerular filtration rate or end-stage kidney disease. The proteome-wide analysis included up to 4907 aptamer-based plasma proteins measured by SomaScan. Results: Among 353153 individuals, 16327 (4.6%) experienced kidney disease progression during a median (IQR) follow-up of 5.1 (3.1;7.2) years. Overall, higher genetic GLP1R gene expression was associated with a lower risk of kidney disease progression in the unadjusted (HR = 0.956, 95% CI [0.921 – 0.993], p-value = 0.022) and fully adjusted models accounting for baseline characteristics, body mass index, and the presence or absence of diabetes (HR = 0.961, 95% CI [0.925 – 0.999], p-value = 0.042). The results were similar in analyses stratified by diabetes or obesity status. Higher genetic GLP1R gene expression was associated with lower body mass index (p-value = 0.0087), fasting glucose (p-value = 0.040), and changes in metabolic plasma proteins including the downregulation of leptin (p-value = 0.0046). Conclusion: Higher genetic GLP1R gene expression was associated with a lower risk of kidney disease progression, even after accounting for its effects on body weight and glycemic control, supporting the role of pleiotropic nephroprotective mechanisms. Funding: NIDDK Support, Veterans Affairs Support