Cell type-stratified immunogenetic framework reveals immune drivers and therapeutic targets in kidney stone disease.

Despite growing recognition of immune involvement in kidney stone disease (KSD), its immunogenetic basis remains unclear. We applied a cell type-stratified immunogenetic framework, integrating single-cell cis-expression quantitative trait loci (cis-eQTL) data from the OneK1K immune atlas, to identify gene-cell type associations across four anatomical KSD subtypes. This approach revealed 80 colocalized gene-cell type pairs with strong genetic support. Natural killer (NK) cells and CD4+ naive/central memory T cells emerged as major contributors to disease risk, with consistent associations observed for BCR-NK cells and RGS14-CD4+/CD8+ T cells across all KSD subtypes. Functional and network analyses highlighted roles for MHC class II antigen presentation and T cell activation, implicating adaptive immunity in pathogenesis. Prioritized genes showed pleiotropic links to renal function, inflammation, and mineral metabolism-for example, RGS14 was associated with improved eGFR and reduced urinary citrate; GPX1 with impaired renal function and elevated CRP; HCG25 and DGKD with higher calcium and uric acid. Clinical complication mapping further implicated these targets in osteoporosis, hypertension, and systemic inflammation. A multi-domain prioritization identified seven top targets-RGS14, BCR, PRR3, HIST1H2BG, SLC44A4, POU5F1, and CTSS-as clinically actionable. These insights may inform future strategies for risk stratification, early detection, and immune-targeted intervention in KSD.