Does rs477155 Stratify Glucocorticoid Toxicity in IgA Nephropathy?

We read with interest the genome-wide pharmacogenomic analysis published in JASN by Xu et al.1 in IgA nephropathy, which identifies rs477155, an intronic cytidine deaminase variant, as a determinant of methylprednisolone responsiveness in the randomized Trial of Efficacy and Safety of TArgeted vs. Standard-dose Glucocorticoid regimens In Nephropathy (TESTING) cohort and replicates the signal in an independent glucocorticoid-treated IgA nephropathy cohort. The functional data suggesting nuclear receptor subfamily 3 group C member 1 (NR3C1)–mediated regulation of cytidine deaminase add mechanistic plausibility. However, several questions arise regarding how rs477155 might be used to personalize systemic glucocorticoid therapy. The 2025 Kidney Disease Improving Global Outcomes IgA nephropathy guideline recommends that, when systemic glucocorticoids are selected, a reduced-dose regimen be combined with antimicrobial prophylaxis—highlighting that benefit must be balanced against infection and other toxicities.2 The TESTING trial similarly reported higher rates of serious adverse events with high-dose methylprednisolone, prompting adoption of reduced-dose protocols.3 First, did rs477155 genotype stratify glucocorticoid-related harms in TESTING, particularly serious infection? This seems clinically important because Xu et al. estimate a number needed to genotype of four to prevent one treatment failure, and rs477155 was linked to immune-related phenotypes in their phenome-wide analyses. Genotype-specific absolute risks (or risk differences) for serious adverse events would complement remission estimates and help interpret net clinical benefit. Second, proteinuria reduction appeared comparable between full-dose and reduced-dose regimens across rs477155 genotypes. It would therefore be informative to know whether dose modifies any genotype–toxicity association. A genotype-by-dose analysis of serious adverse events could clarify whether rs477155 might inform dosing, monitoring intensity, or prophylaxis strategies. We believe that these additional analyses would strengthen the clinical interpretation of rs477155 and support prospective evaluation of genotype-guided glucocorticoid therapy in IgA nephropathy.