LAUSR

The late-onset (over 48 hours after ICU admission) acute respiratory distress syndrome (ARDS) is associated with shorter survival time and higher mortality; however, the underlying molecular targets remain unclear. Since WNT gene family is known to drive inflammation, immunity and tissue fibrosis, all of these are closely related to the pathogenesis and prognosis of ARDS, we aim to investigate the associations of WNT family with late-onset ARDS and 28-day survival. The genetic (N=380), epigenetic (N=185), transcriptional (N=160), and protein (N=300) data of ARDS patients were extracted from the Molecular Epidemiology of ARDS (MEARDS) cohort. We used sure independence screening to identify late-onset related genetic biomarkers and constructed a 8-SNPs based genetic score, which was associated with ARDS late-onset risk (OR=2.72, P=3.81×10-14) and survival (HR=1.28, P=0.008). The associations were further externally validated in the Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR) (ORlate-onset=2.49, P=0.006; HRsurvival=1.87, P=0.045) and the Molecular Epidemiology of Severe Sepsis in the ICU (MESSI) (ORlate-onset=4.12, P=0.026; HRsurvival=1.45, P=0.036). Further, we functionally interrogated the 6 mapped genes of 8 SNPs in the multi-omics data, and noted associations of WNT9A in epigenetic (ORlate-onset=2.95, P=9.91×10-4; HRsurvival=1.53, P=0.011) and protein data (ORlate-onset=1.42, P=0.035; HRsurvival=1.38, P=0.011). The mediation analysis indicated the effects of WNT9A on ARDS survival were mediated by late-onset (HRindirect=1.12, P=0.014 for genetic data; HRindirect=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, which provide clues for ARDS treatment.