Authors’ Reply: Does rs477155 Stratify Glucocorticoid Toxicity in IgA Nephropathy?

We appreciate the thoughtful comments from Yan et al.1 regarding our study,2 published in JASN, and their focus on the potential of rs477155 to individualize systemic glucocorticoid therapy in IgA nephropathy. In response to their questions, we specifically examined whether rs477155 is associated with glucocorticoid-related serious adverse events (SAEs), including serious infections requiring hospitalization, and whether methylprednisolone dose modifies these associations. In The Therapeutic Effects of Steroids in IgA Nephropathy Global study cohort, we assessed the relationship between rs477155 genotype and the overall incidence of SAEs (n=16), with particular attention to serious infections requiring hospitalization (n=8). Across rs477155 genotypes, there was no significant difference in the risk of total SAEs (GG genotype versus GA genotype versus AA, 15% versus 13% versus 7%, respectively, P = 0.6) or serious infections requiring hospitalization (6% versus 8% versus 3%, respectively, P = 0.9). Thus, in contrast to its association with treatment response, rs477155 did not stratify glucocorticoid toxicity in this dataset. Because Yan et al. asked whether dose might interact with genotype to influence toxicity, we further performed stratified analyses according to methylprednisolone regimen (full dose versus reduced dose). Within each dosing stratum, rs477155 genotype was not significantly associated with SAEs, and there was no evidence of a genotype-by-dose interaction on SAE risk. These findings suggest that, within the power of our study, rs477155 does not currently support genotype-based tailoring of glucocorticoid dose, monitoring intensity, or prophylaxis strategies for toxicity. These null safety findings must be interpreted in the context of limited statistical power, as the number of SAEs and serious infections within each genotype subgroup was relatively small. The Kidney Disease Improving Global Outcomes 2025 guideline emphasizes reduced-dose glucocorticoids with antimicrobial prophylaxis to improve the benefit–risk balance,3 underscoring the importance of robust safety data when considering pharmacogenomic implementation. Larger, prospectively powered studies that integrate rs477155 with other clinical and genetic predictors will be essential to determine whether genotype-guided glucocorticoid therapy in IgA nephropathy can simultaneously optimize efficacy and minimize toxicity.