Integrating multiple omics approaches to identify AIF1 as a protective factor in IgA nephropathy

IgA nephropathy (IgAN) is the most prevalent primary glomerular disease worldwide, and its diagnosis still relies on invasive kidney biopsy. To identify noninvasive biomarkers and therapeutic targets, we applied a multi-ancestry Mendelian randomization (MR) framework using proteome-wide association data from an Icelandic population, with validation in independent Fenland and United Kingdom cohorts, followed by transcriptomic, single-cell RNA sequencing (scRNA-seq), and cell-cell communication analyses. Nineteen candidate proteins were identified, and Bayesian colocalization supported a shared genomic region for eight, including AIF1. Transcriptomic analysis revealed downregulation of AIF1 in peripheral blood mononuclear cells from patients with IgAN, and scRNA-seq localized this depletion to dendritic cells (DCs), with partial restoration 150 days after tonsillectomy. Clinical phenotype MR showed inverse associations between AIF1 and hematuria and albuminuria, and enzyme-linked immunosorbent assay (ELISA) showed reduced circulating AIF1 in patients. AIF1 may protect against IgAN through DC-mediated antigen presentation, representing a candidate noninvasive biomarker and therapeutic target.