Genetic Pathway Dysregulation is Both Shared and Distinct in Sepsis-Associated and Trauma-Associated ARDS

Abstract Rationale: Acute respiratory distress syndrome (ARDS) is a complex trait influenced by both environmental insults and underlying genetic susceptibility. Sepsis and trauma are two environmental exposures that precede ARDS development, yet the genetic pathways implicated in ARDS following these insults remain unknown. We sought to determine which genetic signaling pathways were shared in sepsis-associated and trauma-associated ARDS by using pathway enrichment analysis to understand the underlying pathophysiology and to identify future therapeutic targets. Methods: We enrolled critically ill subjects with sepsis (n=2,048) or trauma (n=1,222) in separate prospective cohort studies. All sepsis subjects fulfilled Sepsis-3 consensus criteria. All trauma subjects presented within 24-hours of severe trauma with an injury severity score >15 and survived for at least 24 hours. We extracted DNA from whole blood and ascertained genotype via Affymetrix Axiom TxArrayv1. Subjects were phenotyped for ARDS via Berlin criteria while invasively ventilated within 6 days of ICU admission. We applied multivariable logistic regression to test the association of single nucleotide polymorphism (SNP) genotype with ARDS risk adjusting for age, sex, and principal component-determined genetic ancestry in an additive model. We conducted a functional pathway enrichment analysis using SNPs that demonstrated association with ARDS (p=0.01) using QIAGEN Ingenuity Pathway Analysis for genes only. A p-value less than 0.05 as calculated by the Benjamini-Hochberg method was used to determine the statistical significance for each pathway. Results: ARDS occurred in 880 (43%) genotyped sepsis subjects and 279 (23%) genotyped trauma subjects. In the sepsis cohort, the protein citrullination (p=1.40x10-3), IL-27 signaling (p=9.30x10-3), and STAT3 signaling (p=9.30x10-3) pathways demonstrated the strongest enrichment (Table). The IL-6 signaling (p=4.19x10-2) and the potassium channel signaling (p=4.11x10-2) pathways were also enriched in sepsis. In the trauma cohort, the synaptogenesis signaling (p=9.94x10-7), glutaminergic receptor signaling (p=9.94x10-7), protein kinase A signaling (p=2.70x10-4), and Rho-GTPase signaling (p=8.89x10-4) pathways demonstrated significant enrichment. The potassium channel signaling (p=7.10x10-3) pathway was also enriched in trauma-associated ARDS. Conclusion: Sepsis-associated and trauma-associated ARDS demonstrated enrichment of both shared and distinct genetic pathways. The STAT3 pathway, which was enriched in the sepsis population, is therapeutically targeted by baricitinib in SARS-CoV-2 ARDS. In both populations, there was genetic dysregulation of the potassium channel signaling pathways. Prior work has implicated voltage-gated potassium channels in pulmonary vascular tone and pulmonary hypoxic vasoconstriction. These findings warrant further investigation to identify novel drug targets from the canonical pathways across all environmental causes of ARDS.