Identification of IL7R as a key genetic risk locus in childhood steroid-sensitive nephrotic syndrome and IgA nephropathy.

Abstract / Summary

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is a common childhood glomerular disorder characterized by corticosteroid responsiveness, yet frequent relapses and steroid dependence lead to long-term complications. While GWAS have identified genetic risk loci for pSSNS, its shared genetic architecture with immune-mediated glomerulopathies like IgA nephropathy (IgAN) remains unclear. We performed integrative genetic analyses combining GWAS data from pSSNS (2,440 cases/36,023 controls) and IgAN (10,146 cases/28,751 controls) through meta-analysis and conjunctional false discovery rate (conjFDR) approaches. Findings were replicated in an independent Chinese pSSNS cohort (501 cases/2,506 controls). Transcriptomic profiling of peripheral blood and renal tissues, supplemented by single-cell RNA sequencing, elucidated molecular mechanisms. Meta-analysis identified nine genome-wide significant loci (P < 5×10-8), including five novel regions at 1q23.1, 1p36.13, 5p13.2, 10q21.3, and 10q24.1. ConjFDR analysis revealed 19 pleiotropic loci, with the 5p13.2 (IL7R) locus confirmed by both methods. This signal was replicated in an independent Chinese pSSNS cohort. Transcriptomic analyses using bulk RNA sequencing further revealed IL7R dysregulation associated with steroid response in pSSNS and with disease status in IgAN. Moreover, single-cell RNA sequencing highlighted IL7R dysregulation in CD4+ and CD8+ T cells and NK cells in nephrotic syndrome patients. Our study establishes IL7R as a key shared genetic risk locus in pSSNS and IgAN, supported by multi-omics evidence of immune cell-specific dysregulation. These findings implicate IL7R-mediated T cell homeostasis in the pathogenesis of both disorders, nominating this pathway for targeted therapeutic development.

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