Deleterious variants in LTBP4 are associated with severe pediatric sepsis.

Background: Sepsis is a leading global health burden in children, and its unavoidable heterogeneity has hindered providing therapies beyond antibiotics and supportive care. Recently, we identified four computable phenotypes showing distinct cytokine profiles, clinical outcomes, and therapeutic response characteristics (PedSep-A, B, C, and D) in a multicenter pediatric sepsis cohort.

Methods: In the cohort data, we collected whole-exome sequencing data and identified rare variants associated with PedSep-D phenotype by conducting a gene-based analysis in an aggregated fashion.

Results: As a result, one whole-exome significant gene (LTBP4) and two suggestive significant genes (PLA2G4E, CCDC157) showed association with PedSep-D, the phenotype characterized by the most severe outcomes and highest inflammation. The associated variants in LTBP4 were enriched for predicted deleterious effects based on established functional prediction metrics. All three associated genes are implicated in inflammation and immune cell activation based on existing gene function and expression data. Although the circulating cytokine profiles were overlapping between the rare variant carriers, we also identified gene-specific cytokine changes.

Conclusion: Altogether, our study provides valuable insights into the genetic architecture of a pediatric sepsis phenotype with the highest inflammation level and the most severe outcomes, highlighting potential candidate genes and pathways for further biomarker and therapeutic studies.

Impact: Pediatric sepsis exhibits substantial heterogeneity, with genetic variation contributing to this variability. Rare variants in LTBP4 are significantly associated with the most severe pediatric sepsis phenotype (PedSep-D), while variants in PLA2G4E and CCDC157 show associations with this phenotype in suggestive significance. Expands on the concept of sepsis phenotypes (PedSep-A, B, C, D) by incorporating genetic insights, moving beyond clinical and cytokine profiles to uncover molecular drivers. Opens new avenues for mechanistic studies to understand the genetic underpinnings of severe inflammation and immune activation in sepsis.