Endothelial Vasoactive Pathways and Renal Outcomes: A Drug-Target Mendelian Randomization and Transcriptome-Wide Association Study

作者：Yixin Ma, Lubin Xu, Yitao Lin, Jiahao Zhu, Jin Liu, Li Wang, Limeng Chen · 发表于：Kidney Diseases · 年份：2025 · DOI：10.1159/000548430 · 被引用次数：2 · 研究领域：Chronic Kidney Disease and Diabetes、Genetic Associations and Epidemiology、Renal and Vascular Pathologies

<p>Introduction: Endothelium-mediated regulation of vascular tone plays a crucial role in modulating vascular functions, especially in the kidney, a highly vascularized organ. Therapeutic interventions targeting this process, such as endothelin axis blockage, have demonstrated positive results across various kidney diseases. However, the long-term effects remain poorly explored. Mendelian randomization (MR) and Transcriptome-Wide Association Study (TWAS) provide an approach to investigate the lifelong effects of genetically determined variations in endothelial vasoactive pathways on renal outcomes, mimicking a naturally occurring randomized controlled trial. Method: The primary outcome is the estimated glomerular filtration rate (eGFR), and secondary outcomes include urine albumin-to-creatinine ratio (UACR), rapid kidney function decline, chronic kidney disease (CKD), and various cardiovascular events. From published Genome-Wide Association Studies (GWASs), we extracted summary statistics, employed the inverse variance weighted method for the main MR analysis, complemented by various sensitivity analyses, and utilized the S-PrediXcan for Transcriptome-Wide Association Study (TWAS) analysis. Result: Genetically predicted eNOS pathway activation correlated with higher eGFR (0.03, 95% CI: 0.01–0.05, p = 6.2e−4), reduced risk of CKD (odds ratio 0.47, 95% CI: 0.34–0.64), and rapid kidney function decline (odds ratio 0.47, 95% CI: 0.31–0.72). Transcriptome association studies...