Comprehensive Analysis of IgA Nephropathy Causal Factors in Plasma Proteins, Immune Cell Types, and Immune Cell Traits

KEY POINTS: Single-cell analysis showed increased complement factor H, endoplasmic reticulum aminopeptidase 2, lectin, mannose binding 2 like, pyrin domain containing 1, iduronidase, and gamma-glutamyl hydrolase expression in mesangial cells. Complement factor H was protective, whereas complement factor H-related protein 1 and endoplasmic reticulum aminopeptidase 2 increased IgA nephropathy risk. Genetic analyses implicated neutrophil and white blood cell counts, along with selected CD4 + T-cell traits, in IgA nephropathy. BACKGROUND: IgA nephropathy remains the most frequent primary glomerular disease worldwide with poor outcomes leading to ESKD. Nevertheless, the causal contributions to its pathogenesis are still not fully understood. METHODS: We conducted a Mendelian randomization (MR) phenome-wide association study to identify potential causal factors of IgA nephropathy, among 791 plasma proteins (European population), 1042 plasma proteins (Asian population), 17 circulating immune cells, and 731 immune cell traits. FinnGen database ( N =412,181, N case=653) of IgA nephropathy was applied for replication. Reverse MR and Bayesian colocalization were performed to consolidate the results. Further mechanistic insights were pursued using pathway enrichment and protein-protein interaction analysis. Further validations were conducted by single-cell transcriptomic analysis and human plasma samples testing. Animal experiments were performed to detect the potential mechanism. RESULTS: MR phenome-wide association study of European protein quantitative trait loci identified complement factor H (CFH) as a significant protective factor for IgA nephropathy (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.45 to 0.65; P = 1.47E-10), whereas CFH-related protein 1 (OR, 1.21; 95% CI, 1.12 to 1.31; P = 8.49E-7) and endoplasmic reticulum aminopeptidase 2 (OR, 1.14; 95% CI, 1.07 to 1.21; P = 7.33×E-6) were risk factors. Five causal proteins were replicated in FinnGen database. Four significant causal proteins were identified in the Asian population. Causal associations were found between higher neutrophil counts and IgA nephropathy risk. Top risk immune cell traits included activated and secreting Treg % cluster of differentiation (CD)4+, CD25hi %CD4+, and absolute counts of T cells. Single-cell transcriptomic analysis revealed elevated expression of CFH, endoplasmic reticulum aminopeptidase 2, lectin, mannose binding 2 like, α -L-iduronidase, and gamma-glutamyl hydrolase in mesangial cells from IgA nephropathy patients, and higher plasma levels of iduronidase and pyrin domain containing 1 (PYDC1) in IgA nephropathy cases. In silico analysis and mice experiments showed PYDC1, caspase1, nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3), and IL1 β were elevated in IgA nephropathy kidneys. CONCLUSIONS: Our study suggested that specific proteins, cell types, and immune traits have causal effects in IgA nephropathy pathogenesis, particularly implicating complement components, PYDC1 and certain CD4 + T-cell subsets as priorities for further mechanistic research and therapeutic development.