Genome-wide association study of susceptibility to acute respiratory distress syndrome

Abstract

IntroductionAcute respiratory distress syndrome (ARDS) is a severe inflammatory process of the lung, often due to sepsis, and poses significant mortality burden in intensive care units. Here we conducted the largest genome-wide association study (GWAS) of sepsis-associated ARDS to identify novel genetic risk loci that can help guide the development of new therapeutic options. MethodsWe performed a case-control GWAS in 716 patients with sepsis-associated ARDS and 4,399 at-risk sepsis controls from three independent studies. Results were meta-analysed across the three studies, with significance set at p<5x10-8. Suggestive associations were declared for variants exhibiting consistent effects, likely to replicate and nominal significance (p<0.05) in all three studies. Prioritised loci were subjected to Bayesian fine mapping, in-silico functional assessments, and gene-based rare variant collapsing analysis using whole exome sequencing (WES) data. Two independent studies with 430 ARDS cases and 1,398 controls served as replication samples. ResultsWe identified a variant showing genome-wide significant association with sepsis-associated ARDS risk intergenic to ANKRD31 and HMGCR, previously linked to cholesterol metabolism. Suggestive associations were found for eight other variants. The rare exonic variant analysis showed associations between HMGCR and POC5 and sepsis-associated ARDS at nominal level (p<0.05). While no nominal significance was achieved in the two additional validation cohorts, three variants exhibited a consistent direction of effects across all 5 studies. ConclusionA common variant intergenic to ANKRD31 and HMGCR was associated with sepsis-associated ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed.