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

Neurocritical Care, 2026

Bhak Y., Helmy A., Needham E., Menon D., Warrier V., Samanta R., Åkerlund C., Amrein K., Andelic N., Andreassen L., Anke A., Antoni A., Audibert G., Azouvi P., Azzolini M., Bartels R., Barzó P., Beauvais R., Beer R., Bellander B., Belli A., Benali H., Berardino M., Beretta L., Blaabjerg M., Bragge P., Brazinova A., Brinck V., Brooker J., Brorsson C., Buki A., Bullinger M., Cabeleira M., Caccioppola A., Calappi E., Calvi M., Cameron P., Carbayo Lozano G., Carbonara M., Cavallo S., Chevallard G., Chieregato A., Citerio G., Clusmann H., Coburn M., Coles J., Cooper J., Correia M., Čović A., Curry N., Czeiter E., Czosnyka M., Dahyot-Fizelier C., Dark P., Dawes H., De Keyser V., Degos V., Della Corte F., den Boogert H., Depreitere B., Đilvesi ?., Dixit A., Donoghue E., Dreier J., Dulière G., Ercole A., Esser P., Ezer E., Fabricius M., Feigin V., Foks K., Frisvold S., Furmanov A., Gagliardo P., Galanaud D., Gantner D., Gao G., George P., Ghuysen A., Giga L., Glocker B., Golubovic J., Gomez P., Gratz J., Gravesteijn B., Grossi F., Gruen R., Gupta D., Haagsma J., Haitsma I., Helbok R., Helseth E., Horton L., Huijben J., Hutchinson P., Jacobs B., Jankowski S., Jarrett M., Jiang J., Johnson F., Jones K., Karan M., Kolias A., Kompanje E., Kondziella D., Kornaropoulos E., Koskinen L.,  Kovács N., Kowark A., Lagares A.,  Lanyon L., Laureys S., Lecky F., Ledoux D.,  Lefering R., Legrand V., Lejeune A., Levi L., Lightfoot R., Lingsma H., Maas A., Castaño-León A., Maegele M., Majdan M., Manara A., Manley G., Martino C., Maréchal H., Mattern J., McMahon C., Melegh B., Menon D., Menovsky T., Mikolic A., Misset B., Muraleedharan V., Murray L., Negru A., Nelson D., Newcombe V., Nieboer D., Nyirádi J., Olubukola O., Oresic M., Ortolano F., Palotie A., Parizel P., Payen J., Perera N., Perlbarg V., Persona P., Peul W., Piippo-Karjalainen A., Pirinen M., Pisica D., Ples H., Polinder S., Pomposo I., Posti J., Puybasset L., Radoi A., Ragauskas A., Raj R., Rambadagalla M., Helmrich I., Rhodes J., Richardson S., Richter S., Ripatti S., Rocka S., Roe C., Roise O., Rosand J., Rosenfeld J., Rosenlund C., Rosenthal G., Rossaint R., Rossi S., Rueckert D., Rusnák M., Sahuquillo J., Sakowitz O., Sanchez-Porras R., Sandor J., Schäfer N., Schmidt S., Schoechl H., Schoonman G., Schou R., Schwendenwein E., Sewalt C., Singh R., Skandsen T., Smielewski P., Sorinola A., Stamatakis E., Stanworth S., Stevens R., Stewart W., Steyerberg E., Stocchetti N., Sundström N., Takala R., Tamás V., Tamosuitis T., Taylor M., Thibaut A., Ao B., Tenovuo O., Theadom A., Thomas M., Tibboel D., Timmers M., Tolias C., Trapani T., Tudora C., Unterberg A., Vajkoczy P., Vallance S., Valeinis E., Vámos Z., van der Jagt M., Van der Steen G., Naalt J., van Dijck J., van Erp I., van van Essen T., Van Hecke W., van Heugten C., van Veen E., Vyvere T., van Wijk R., Vargiolu A., Vega E., Velt K., Verheyden J., Vespa P., Vik A., Vilcinis R., Volovici V., von Steinbüchel N., Voormolen D., Vulekovic P., Wang K., Whitehouse D., Wiegers E., Williams G., Wilson L., Winzeck S., Wolf S., Yang Z., Ylén P., Younsi A., Zeldovich M., Zeiler F., Zelinkova V., Ziverte A., Zoerle T.

Disease areaApplication areaSample typeProducts
Neurology
Pathophysiology
Plasma
Olink Explore 3072/384

Olink Explore 3072/384

Abstract

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.

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