• Kate F Kernan, Ashley Adkins, Ruchira M Jha, Patrick M Kochanek, Joseph A Carcillo, Robert A Berg, David Wessel, Murray M Pollack, Kathleen Meert, Mark Hall, Christopher Newth, John C Lin, Allan Doctor, Tim Cornell, Rick E Harrison, Athena F Zuppa, Daniel A Notterman, and Rajesh K Aneja.
• Departments of Neurology, Neurological Surgery, Translational Neuroscience, Barrow Neurological Institute, and St. Joseph's Hospital and Medical Center, Phoenix, AZ.
• Shock. 2024 Sep 3.

BackgroundSepsis-associated brain injury is associated with deterioration of mental status, persistent cognitive impairment, and morbidity. The SUR1/TRPM4 channel is a non-selective cation channel that is transcriptionally upregulated in the central nervous system with injury, allowing sodium influx, depolarization, cellular swelling, and secondary injury. We hypothesized that genetic variation in ABCC8 (SUR1 gene) and TRPM4 would associate with central nervous system dysfunction in severe pediatric sepsis.Methods326 children with severe sepsis underwent whole exome sequencing in an observational cohort. We compared children with and without central nervous system dysfunction (Glasgow Coma Scale <12) to assess for associations with clinical characteristics and pooled rare variants in ABCC8 and TRPM4. Sites of variation were mapped onto protein structure and assessed for phenotypic impact.ResultsPooled rare variants in either ABCC8 or TRPM4 associated with decreased odds of central nervous system dysfunction in severe pediatric sepsis (OR 0.14, 95% CI 0.003-0.87), p-value = 0.025). This association persisted following adjustment for race, organ failure, viral infection, and continuous renal replacement therapy (aOR 0.11, 95% CI 0.01-0.59, p-value = 0.038). Structural mapping showed that rare variants concentrated in the nucleotide-binding domains of ABCC8 and N-terminal melastatin homology region of TRPM4.ConclusionThis study suggests a role for the ABCC8/TRPM4 channel in central nervous system dysfunction in severe pediatric sepsis. While exploratory, the lack of therapies to prevent or mitigate central nervous system dysfunction in pediatric sepsis warrants further studies to clarify the mechanism and confirm the potential protective effect of these rare ABCC8/TRPM4 variants.Copyright © 2024 by the Shock Society.

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