WNT9A Affects Late-Onset Acute Respiratory Distress Syndrome and 28-Day Survival: Evidence from a Three-Step Multiomics Study

Late-onset (more than 48 h after ICU admission) acute respiratory distress syndrome (ARDS) is associated with shorter survival time and higher mortality; however, the underlying molecular targets remain unclear. As the WNT gene family is known to drive inflammation, immunity, and tissue fibrosis, all of which are closely related to the pathogenesis and prognosis of ARDS, we aim to investigate the associations of the WNT family with late-onset ARDS and 28-day survival. Genetic (n = 380), epigenetic (n = 185), transcriptional (n = 160), and protein (n = 300) data of patients with ARDS were extracted from the MEARDS (Molecular Epidemiology of ARDS) cohort. We used sure independence screening to identify late onset-related genetic biomarkers and constructed a genetic score on the basis of eight SNPs, which was associated with risk for late-onset ARDS (odds ratio [OR], 2.72; P = 3.81 × 10^-14) and survival (hazard ratio [HR], 1.28; P = 0.008). The associations were further externally validated in the iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk) (OR_{late onset}, 2.49 [P = 0.006]; HR_survival, 1.87 [P = 0.045]) and MESSI (Molecular Epidemiology of Severe Sepsis in the ICU) (OR_{late onset}, 4.12 [P = 0.026]; HR_survival, 1.45 [P = 0.036]) cohorts. Furthermore, we functionally interrogated the six mapped genes of eight SNPs in the multiomics data and noted associations of WNT9A (WNT family member 9A) in epigenetic (OR_{late onset}, 2.95 [P = 9.91 × 10^-4]; HR_survival, 1.53 [P = 0.011]) and protein (OR_{late onset}, 1.42 [P = 0.035]; HR_survival, 1.38 [P = 0.011]) data. The mediation analysis indicated that the effects of WNT9A on ARDS survival were mediated by late onset (HR_indirect, 1.12 [P = 0.014] for genetic data; HR_indirect, 1.05 [P = 0.030] for protein data). The essential roles of WNT9A in immunity and fibrosis may explain the different trajectories of recovery and dysfunction between early- and late-onset ARDS, providing clues for ARDS treatment.