Genetic Determinants of Steroid Responsiveness in IgA Nephropathy

KEY POINTS: Genetic variant rs477155 near cytidine deaminase identified IgA nephropathy patients with enhanced glucocorticoid response. rs477155 may regulate cytidine deaminase via glucocorticoid receptor, linking genomic variation to steroid sensitivity and individualized treatment optimization. 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 The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study cohort (134 received methylprednisolone and 126 received placebo), assessing the percentage reduction in 24-hour proteinuria at 6 months via genotype-by-treatment interaction models. Replication was performed in an independent cohort of 211 high-risk patients receiving glucocorticoid monotherapy. Functional annotation, expression quantitative trait loci mapping, regulatory analyses, and dual-luciferase reporter assays elucidated the biologic 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 cytidine deaminase [ CDA ]) was replicated in the independent cohort (discovery P = 2.70×10 -6 , replication P = 0.01). In the TESTING study cohort, carriers of the rs477155 GG genotype had significantly higher rates of complete proteinuria remission (odds ratio, 2.5; 95% confidence interval, 1.3 to 4.9; P = 5.00×10 -3 ) and composite clinical remission (odds ratio, 2.8; 95% confidence interval, 1.6 to 4.9; P = 3.13×10 -4 ) at 6 months. Functional analyses revealed that rs477155 acts as a Cis -expression quantitative trait locus for CDA in blood and immune cells and is located within an enhancer region marked by H3K4Me1/H3K27Ac and a glucocorticoid receptor (nuclear receptor subfamily 3 group C member 1 [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 versus 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.