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

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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Publication Details

Journal
Neurocritical Care
Published
2026-07-28
DOI
https://doi.org/10.1007/s12028-026-02575-3
Primary Topic
IL-33, ST2, and ILC Pathways
Type
article
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article

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

Morten Blaabjerg, Endre Czeiter, Ben Glocker, Guy‐Loup Dulière et al.
Neurocritical Care
IL-33, ST2, and ILC Pathways
article

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

Morten Blaabjerg, Endre Czeiter, Ben Glocker, Guy‐Loup Dulière, Alexandra Bražinová, Raimund Helbok, Bram Jacobs, Hugo den Boogert, Arturo Chieregato, Eirik Helseth, Guillermo Carbayo Lozano, Luigi Beretta, Jagoš Golubović, Mike Jarrett, Krisztina Amrein, Nada Anđelić, Ari Ercole, Maurizio Berardino, Guoyi Gao, Monika Bullinger, Romuald Beauvais, Alessio Caccioppola, Đula Đilvesi, Marco Carbonara, Simona Cavallo, Camilla Brorsson, András Büki, Philippe Azouvi, Pablo Gagliardo, Edward Needham, Mark Coburn, Youngjune Bhak, Antonio Belli, Peter Bragge, Romit Samanta, Patrick Esser, Valery L. Feigin, Lasse Andreassen, Véronique De Keyser, David Krishna Menon, Juanita A. Haagsma, Pradeep George, J Dreier, Vincent Degos, Lelde Giga, Maria Luisa Azzolini, Giorgio Chevallard, Vibeke Brinck, Faye Johnson, Maria Rosa Calvi, Pál Barzó, Stefan Jankowski, Alexandre Ghuysen, Francesca Grossi, Marek Czosnyka, Alex Furmanov, Johannes Gratz, Jiyao Jiang, Giuseppe Citerio, Habib Benali, Deepak Gupta, Pedro A. Gómez, Abhishek Dixit, Damien Galanaud, Jamie Cooper, P. Dark, Françesco Della Corte, Claire Dahyot‐Fizelier, Lindsay Horton, Emiliana Calappi, Erzsébet Ezer, Cecilia Åkerlund, Joanne Brooker, Nicola Curry, Dashiell Gantner, Audny Anke, Shirin Frisvold, Hans Clusmann, Bart Depreitere, Manuel Cabeleira, Iain Haitsma, Adel Helmy, Emma Donoghue, Peter Cameron, Anna Antoni, Russell L. Gruen, Gérard Audibert, Benjamin Gravesteijn, Amra Čović, Bo-Michael Bellander, Ronny Beer, Helen Dawes, Peter J. Hutchinson, Jilske Huijben, Ronald Bartels, Kelly Foks, Jonathan Coles, Marta Correia, Martin Fabricius, Varun Warrier
article en

Abstract

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.

Neurocritical Care
Good health and well-being
Openalex Percentile: Top 15%
IL-33, ST2, and ILC Pathways
DOIOpen Access PDFOpenAlex
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