Mendelian randomization and colocalization analysis reveal the role of IL-6 signaling pathway in psoriasis and potential therapeutic targets.

IL-6 signaling is critical in the pathogenesis of several autoimmune diseases, including psoriasis and psoriatic arthritis. This study utilized Mendelian randomization (MR) analysis to investigate the genetic associations between IL-6 signaling, soluble IL-6 receptor (sIL-6R) levels, and psoriasis and its arthritis. Additionally, the therapeutic potential of IL-6R inhibitors was evaluated. The study methodology was validated through positive and negative control analysis, with further confirmation of genetic associations via Bayesian factor colocalization analysis. The MR results indicated that upregulation of IL-6 signaling was positively associated with psoriasis (PIVW = 0.008, 95% CI: 1.16-2.66), whereas elevated sIL-6R levels were negatively associated with psoriasis (PIVW < 0.001, 95% CI: 0.95-0.99). Positive control analysis showed that IL-6R inhibitors effectively reduced the risk of rheumatoid arthritis but increased the risk of atopic dermatitis. In contrast, negative control analysis revealed no significant therapeutic effect on seborrheic dermatitis. Using GWAS data from multiple databases, IL-6R inhibitors were identified as being associated with a reduced risk of psoriasis and psoriatic arthritis. Colocalization analysis highlighted the rs4129267 genetic variant as strongly linked to the therapeutic effects of IL-6R inhibitors on psoriasis (P < 0.001, 95% CI: 0.37-0.74). These findings underscore the crucial role of IL-6 signaling in the development of psoriasis and psoriatic arthritis and provide robust genetic evidence supporting the therapeutic potential of IL-6R inhibitors. By identifying genetic determinants of disease susceptibility and potential biomarkers of treatment response, this study provides valuable clinical insights and guidance for optimizing treatment strategies for psoriasis.