CIRCULATING INFLAMMATORY PROTEINS IN DRUG-INDUCED ANAPHYLACTIC SHOCK: EVIDENCE FROM MULTIVARIABLE MENDELIAN RANDOMIZATION AND MULTIOMICS INTEGRATION.

Background : Drug-induced anaphylactic shock (DIAS) remained a critical clinical challenge due to increased drug use and novel hypersensitivity mechanisms. The role of circulating inflammatory proteins in DIAS remained unclear. Methods: We applied multivariable Mendelian randomization (MR) to explore the associations between specific inflammatory proteins and DIAS, drawing on recent findings from genome-wide association studies. Circulating inflammatory protein data were obtained from a cohort of European ancestry comprising 14,824 samples, while data on DIAS were sourced from the FinnGen consortium, including 20,806 cases and 411,845 controls. To strengthen our findings, we conducted complementary analyses such as colocalization (COLOC), enrichment studies, drug screening, and molecular docking. Results: MR analysis identified significant associations between inflammatory proteins and DIAS. CD40L exhibited a protective effect (OR = 0.69, 95% CI: 0.4951-0.9578, P = 0.027) and high colocalization probability (58%). CXCL10 (OR = 1.51, 95% CI: 1.0075-2.2549, P = 0.046) and CCL3 (OR = 2.08, 95% CI: 1.0079-4.3072, P = 0.048) significantly increased risk. Drug screening and enrichment analyses further elucidated underlying molecular mechanisms. Conclusions : This study identified novel associations between inflammatory proteins and the risk of anaphylaxis, providing insights for targeted prediction and therapeutic strategies.