The genomic landscape of Acute Respiratory Distress Syndrome: a meta-analysis by information content of genome-wide studies of the host response

Abstract Acute respiratory distress syndrome (ARDS) is a clinically defined syndrome of acute hypoxaemic respiratory failure secondary to non-cardiogenic pulmonary oedema. It arises from a diverse set of triggers and encompasses marked biological heterogeneity, complicating efforts to develop effective therapies. An extensive body of recent work (including transcriptomics, proteomics, and genome-wide association studies) has sought to identify proteins/genes implicated in ARDS pathogenesis. These diverse studies have not been systematically collated and interpreted. To solve this, we performed a systematic review and computational integration of existing omics data implicating host response pathways in ARDS pathogenesis. We identified 40 unbiased studies reporting associations, correlations, and other links with genes and single nucleotide polymorphisms (SNPs), from 6,856 ARDS patients. We used meta-analysis by information content (MAIC) to integrate and evaluate these data, ranking over 7,000 genes and SNPs and weighting cumulative evidence for association. Functional enrichment of strongly-supported genes revealed cholesterol metabolism, endothelial dysfunction, innate immune activation and neutrophil degranulation as key processes. We identify 51 hub genes, most of which are potential therapeutic targets. To explore biological heterogeneity, we conducted a separate analysis of ARDS severity/outcomes, revealing distinct gene associations and tissue specificity. Our large-scale integration of existing omics data in ARDS enhances understanding of the genomic landscape by synthesising decades of data from diverse sources. The findings will help researchers refine hypotheses, select candidate genes for functional validation, and identify potential therapeutic targets and repurposing opportunities. Our study and the publicly available computational framework represent an open, evolving platform for interpretation of ARDS genomic data.