Mendelian Randomization Analysis of the IL-1 Cytokine Family Proteins Identifies IL1RL1 as a Potential Causal Contributor to Traumatic Brain Injury Prognosis

Background Traumatic brain injury (TBI) is a leading preventable cause of death and disability worldwide. Inflammatory mechanisms contribute to secondary brain injury, and the interleukin-1 (IL-1) cytokine family has emerged as a potential contributor. However, whether circulating IL-1-family cytokines causally influence TBI outcomes remains unknown. Methods We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effects of circulating IL-1-family protein levels on TBI outcomes, using inverse-variance weighting (IVW) as the primary analytic method and publicly available genome-wide association study summary statistics. Results Higher genetically predicted circulating IL1RL1 (soluble ST2) levels were associated with an increased risk of unfavorable TBI outcomes (IVW β = 0.22, standard error [SE] = 0.084, P = 0.010), although we were underpowered to test the reverse direction. Sensitivity analyses demonstrated consistent effect estimates with no evidence of horizontal pleiotropy. Conclusions These findings provide genetic evidence that elevated circulating IL1RL1 levels are causally linked to worse TBI outcomes. This suggests the IL-33/IL1RL1 axis as a mechanistically relevant, and potentially modifiable, therapeutic target for improving recovery after TBI.