Kate Kernan, MD
Assistant Professor
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States
Disclosure information not submitted.
Ashley Adkins, MD
Resident Physician
Children's Hospital of Pittsburgh, United States
Disclosure information not submitted.
Joseph Carcillo, MD
Professor
Children's Hospital of Pittsburgh of UPMC, United States
Disclosure information not submitted.
Ruchira Jha, MD, MSc
Associate Professor
Barrow Neurological Institute, United States
Disclosure information not submitted.
.jpg "Patrick Kochanek, MD, MCCM photo")
Patrick Kochanek, MD, MCCM
Director, Safar Center for Resuscitation Research
UPMC Presbyterian
Pittsburgh, Pennsylvania
Disclosure information not submitted.
Rajesh Aneja, MD, FCCM
Professor, Pediatrics and Critical Care Medicine. Medical Director, PICU.
UPMC Children's Hospital of Pittsburgh, United States
Disclosure information not submitted.
Title: Rare TRMP4 & ABCC8 Variants Associate with Decreased Incidence of CNS Failure in Pediatric Sepsis
Introduction: The mechanisms of cognitive dysfunction in sepsis are poorly understood. Genetic variations in sulfonylurea-receptor 1 (SUR1, gene: ABCC8) and transient receptor potential cation channel subfamily M-4 (TRPM4) associate with outcome in traumatic brain injury and form non-selective cation channels that are upregulated during injury in astrocytes, endothelium, glia and neurons contributing to edema. Hypothesizing similar mechanisms in sepsis CNS dysfunction, we evaluated associations between TRPM4 and ABCC8 variation and CNS failure in pediatric sepsis.
Methods: 330 children completed whole exome sequencing in the PHENOMS severe sepsis cohort. Children with and without CNS failure (GCS < 12 without sedatives) were compared by demographics, clinical characteristics and presence of rare variants (Minor Allele Frequency < 0.05) in ABCC8 (R298C, I693T, A726T, C805Y, R992P, C1128S, H1537PfsTer22, V1539M, R1568Q) or TRPM4 (V57WfsTer2, R252H, Q295H, E330K, E497Q, W525Ter, F533V, D561A, R719Q, G737R, C763_R766del, G844D, W940C, S1143G, P1204L). Variants were mapped to protein structure. We constructed a multivariable logistic regression model using forward and backward selection to predict CNS failure, incorporating variant status, demographic and clinical characteristics (p-value < 0.1 in univariate testing).
Results: CNS failure occurred in 57 children and in univariate testing associated with black race and mortality (p-value < 0.05). Those with CNS failure also had decreased odds of carrying rare variants (in ABCC8 OR:0, 95%CI: 0 – NA, p-value = 0.37; in TRPM4 OR:0.211, 95%CI 0.009 – 1.028, p-value = 0.067; ABCC8 or TRPM4 OR: 0.135 95%CI: 0.003 – 0.845, p-value = 0.026). Seven of nine ABCC8 variants occurred in regulatory nucleotide binding domains. The 15 TRMP4 variants occurred across the length of the protein. In multivariable model, rare variant status remained significantly associated with CNS failure after adjustment for age, mortality, mechanical ventilation, viral infection and black race (OR 0.086, 95%CI: 0.005 – 0.446).
Conclusions: Our study suggests CNS failure was associated with a decreased odds of rare genetic variation in ABCC8 and TRPM4. Our current focus is to understand the impact of these variants on SUR1 channel function and the development of CNS dysfunction in severe pediatric sepsis.