Genetic Determinants of Steroid Responsiveness in IgA Nephropathy

Background: Glucocorticoid therapy improves outcomes in high-risk IgA nephropathy but shows variable efficacy and adverse effects, potentially influenced by genetic factors. Methods: We conducted a genome-wide pharmacogenomic analysis in 260 biopsy-confirmed patients with IgA nephropathy from the Chinese TESTING cohort (134 received methylprednisolone, 126 received placebo), assessing the percentage reduction in 24-hour proteinuria at six months via genotype-by-treatment interaction models. Replication was performed in an independent cohort of 211 high-risk patients receiving glucocorticoid monotherapy. Functional annotation, eQTL mapping, regulatory analyses, and dual-luciferase reporter assays elucidated the biological relevance of candidate loci. Results: Genome-wide analysis identified three loci with suggestive genotype-by-treatment interaction ( P < 5.00×10 -6 ), of which rs477155 (chromosome 1, intronic to CDA ) was replicated in the independent cohort (discovery P = 2.70×10 -6 , replication P = 0.01). In the TESTING cohort, carriers of the rs477155 GG genotype had significantly higher rates of complete proteinuria remission (OR 2.5, 95% CI 1.3–4.9, P = 5.00×10 -3 ) and composite clinical remission (OR 2.8, 95% CI 1.6–4.9, P = 3.13×10 -4 ) at six months. Functional analyses revealed that rs477155 acts as a cis- eQTL for CDA in blood and immune cells and is located within an enhancer region marked by H3K4Me1/H3K27Ac and a glucocorticoid receptor (NR3C1) binding site. Bioinformatics, dual-luciferase reporter assay , and RNA-seq analyses indicated that NR3C1 may directly regulate CDA expression, with rapid upregulation of CDA observed in blood after dexamethasone stimulation (9.84±0.52 vs. 10.50±0.55, P = 7.41×10 -23 ). Phenome-wide association studies further linked rs477155 and CDA to a spectrum of immune and kidney traits, including acute tubulointerstitial nephritis ( P = 7.4×10 -11 ), nephritic syndrome ( P = 2.7×10 -8 ), asthma ( P = 2.5×10 -21 ), and rheumatoid arthritis ( P = 2.1×10 -12 ). Conclusions: In this study, rs477155 was suggestively associated with glucocorticoid responsiveness in IgA nephropathy, potentially via a suggested NR3C1-regulated CDA pathway.