Elucidating Genetic and Immunological Pathways Mediated by Sodium-Glucose Transporter 2 Inhibitors in Reducing Gout Risk: A Two-Step Mendelian Randomization Study.

While sodium-glucose transporter 2 inhibitors (SGLT2i) demonstrate urate-lowering effects, their causal role in Gout prevention remains controversial. This study employs advanced Mendelian randomization (MR) techniques to dissect immune-mediated mechanisms underlying this relationship. Using bidirectional two-sample MR and mediation analysis, we analyzed genetic instrument variables for SGLT2i (10 single-nucleotide polymorphisms, F-statistic >20), Gout risk (6,810 cases/477,788 controls), and 731 immune cell phenotypes. Pleiotropy and heterogeneity were also assessed to ensure robustness. The study confirmed a significant indirect effect of SGLT2i, which exhibited a 2.6% reduced Gout risk (Odds Ratio [OR]: 0.9738, 95% confidence interval [CI] = 0.9623, 0.9854, P = 1.12e-05). Thirty-five immune cell phenotypes were identified as significantly affecting Gout development, with key phenotypes such as CD86 on myeloid Dendritic cell (DC) (OR: 0.9966; 95% CI = 0.9930, 0.9995), contributing to 12.8% of the overall mediation effect. No evidence of heterogeneity or pleiotropy was detected and reverse-direction MR corroborated these findings. Our study first established SGLT2i as Gout-protective agents through DC-mediated immunomodulation, offering mechanistic insights for targeted prevention strategies in clinical practice.