The Role of Angiopoietin-Like Proteins 3 and 4 and Their Target Lipases in CKD: A Drug-Target Mendelian Randomization Study

Rationale & Objective Angiopoietin-like proteins (ANGPTL) 3 and 4 modulate lipoprotein metabolism through inhibition of lipases. Reduced activity of ANGPTL3 and ANGPTL4 improves kidney function in mice. This study aimed to investigate the causal relationships of ANGPTLs and their lipase targets with chronic kidney disease (CKD) in humans. Study Design A drug-target Mendelian randomization (MR) study and single-cell RNA sequencing analyses. Setting & Participants Participants of European, East Asian, and African ancestry in the All of Us, Penn Medicine Biobank, and genome-wide association studies; kidney samples from the Susztaklab Kidney Biobank. Exposures Genetically proxied ANGPTL3, ANGPTL4, lipoprotein lipase, endothelial lipase, and hepatic lipase. Outcomes CKD risk and estimated glomerular filtration rate based on serum creatinine (eGFRcrea). Analytical Approach Genetic variants were used as proxies for ANGPTLs and their lipase targets, and their associations with CKD risk and eGFRcrea were assessed. Relevant gene expression across kidney cell types and between CKD patients and controls was also characterized. Results In total, 186,388 CKD cases among 2,369,738 individuals were included. For each 1-standard deviation (SD) decrease in triglycerides, genetically proxied ANGPTL3 inhibition, ANGPTL4 inhibition, and lipoprotein lipase enhancement were associated with lower CKD risk (odds ratio (OR) 0.76 [95% confidence interval 0.69 to 0.84], 0.78 [0.68 to 0.91], and 0.86 [0.83 to 0.90]) and higher eGFRcrea. For each 1-SD decrease in high-density lipoprotein cholesterol, genetically proxied endothelial lipase enhancement was associated with lower CKD risk (OR 0.89 [0.82 to 0.96]) and higher eGFRcrea specifically in people of European ancestry. Genetically proxied hepatic lipase enhancement was associated with lower CKD risk (OR 0.83 [0.74 to 0.92]) specifically in people of African ancestry. ANGPTL3 , ANGPTL4 , and LPL were differentially expressed across kidney cell types and between CKD patients and controls. Limitations Rigorous MR assumptions; non-kidney-specific instrument selection; potential misclassification of CKD. Conclusions Genetic reductions in ANGPTL3 and ANGPTL4 reduce CKD risk by enhancing lipase activity. ANGPTL3, ANGPTL4, and their target lipases (lipoprotein lipase and endothelial lipase) are potentially promising therapeutic targets for CKD prevention and treatment.