Identification of potential therapeutic targets for complement-associated glomerular diseases using Mendelian randomization

The complement system is a crucial part of the innate immune response, involved in various glomerular diseases through its activation in different pathways. Uncontrolled complement activation plays a key role in common glomerular diseases such as IgA nephropathy (IgAN), membranous nephropathy (MN), and diabetic nephropathy (DN). Understanding the specific role of complement activation in these conditions is critical for the development of targeted therapies. This study employed Mendelian randomization to examine the causal role of complement components IgAN, MN, and DN. By utilizing protein Quantitative Trait Loci data, gene expression analysis, protein-protein interaction networks, and enrichment analysis, we sought to investigate the involvement of complement pathways and identify potential therapeutic targets. Genetically elevated plasma complement factor H-related protein 1 (CFHR1) levels demonstrated a significant causal association with increased IgAN risk (inverse variance weighting odds ratio 1.239, 95% confidence interval 1.084-1.417; false discovery rate [FDR]-adjusted P = .002). CFHR1 was expressed in renal T cells and plasma cells, and its protein-protein interaction network enriched immune/inflammatory pathways. No complement proteins showed significant causal associations with MN after FDR correction. Genetically elevated plasma complement factor D (CFD), levels were causally associated with increased DN risk (inverse variance weighting odds ratio 1.264, 95% confidence interval 1.090-1.465; FDR-adjusted P = .002). CFD was expressed in renal macrophages, and its network enriched inflammatory processes. Targeting complement regulators like CFHR1 and CFD may provide new therapeutic opportunities for IgAN and DN.