Causal relationship between PCSK9 inhibitor and primary glomerular disease: a drug target Mendelian randomization study

• DOI: 10.3389/fendo.2024.1335489
• Publication Date: 2024-03-06T04:54:48Z
• Authors: Hangyu Duan; Yue Shi; Qi Zhang; Xiujie Shi; Yifan Zhang; Jing Liu; Yu Zhang
• Keywords: Mendelian Randomization; PCSK9

Background Successive observational studies have highlighted low-density lipoprotein cholesterol (LDL-C) as a standalone risk factor for the progression of chronic kidney disease (CKD) to end-stage renal disease. Lowering LDL-C levels significantly reduces incidence atherosclerotic events in patients with progressive CKD. Recent research indicates that proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors not only effectively lower CKD but also exhibit therapeutic potential autoimmune diseases such systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis. However, role PCSK9 (PCSK9i) treating beyond lowering remains uncertain. Therefore, this study employs drug-targeted Mendelian randomization (MR) investigate causal impact PCSK9i on primary glomerular IgA nephropathy (IgAN), membranous (MN), nephrotic syndrome (NS). Methods Single-nucleotide polymorphisms (SNPs) linked were sourced from Global Lipids Genetics Consortium genome-wide association (GWAS). Genes situated proximity 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), served proxies inhibition these targets. The link between disorders was discovered using drug-target MR studies. HMGCR inhibitor, drug target statins, utilized comparative analysis PCSK9i. Primary outcomes included assessment IgAN, MN, NS, coronary heart positive control. Results PCSK9, proxied genetically, found reduce IgAN [odds ratio, OR (95% confidence interval, CI) = 0.05 (−1.82 1.93), p 2.10 × 10 −3 ]. Conversely, associated an increased NS [OR 1.78 (1.34–2.22), 0.01]. Similarly, (HMGCRi) demonstrated reduction (95%CI) 0.0032 (−3.58 3.59), 1.60 −3) . Conclusions markedly decreased suggesting mechanism their effect LDL-C. NS. On other hand, HMGCRi appears serve protective against IgAN. may pose necessity cautious application further into impacts various diseases.