Rare genetic variant risks in patients with sepsis-associated acute respiratory distress syndrome

BackgroundAcute respiratory distress syndrome (ARDS) is a complex, heterogeneous, and deadly condition often resulting from pulmonary lesions due to sepsis, among other causes. There is a lack of targeted therapies to specifically treat the patients. Common genetic factors in the population (frequency >1%) have been associated with ARDS susceptibility, but systematic genetic screens of the role of rare genetic variants are lacking. We used the network of known molecular interactions to identify ARDS risks from clusters of biologically related genes containing qualifying variants (QVs) with frequency <1% likely affecting function. MethodsWe conducted whole-exome sequencing in sepsis patients from the GEN-SEP cohort (n=822, of which 272 developed ARDS). A network-based heterogeneity clustering algorithm was used to identify significant gene clusters (p<1x10-5). Gene-set enrichment analysis and logistic regression models aggregating QVs were used for characterization of gene clusters and findings validation. ResultsWe identified 19 significant clusters (plowest=3.29x10-10), each containing an average of 102 genes (11.6% mean similarity). QVs in eight gene clusters were associated with sepsis-associated ARDS (plowest=2.35x10-4) but were not associated with 28-day survival. Clusters were enriched in several biological pathways, notably the Interferon signaling and Toll-like receptor cascades. ConclusionsThese results support a marked genetic heterogeneity underlying ARDS susceptibility and the presence of risk variants involving multiple biological processes that are associated with sepsis outcomes. This evidence paves the way for future development of preventive and therapeutic approaches targeting those pathways to reduce the risk for sepsis-associated ARDS.