Genome-wide association study of susceptibility to acute respiratory distress syndrome
Abstract
Introduction
Acute 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.
Methods
We 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 atp<5×10-8. 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-silicofunctional 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.
Results
We identified a variant showing genome-wide significant association with sepsis-associated ARDS risk intergenic toANKRD31andHMGCR, previously linked to cholesterol metabolism. Suggestive associations were found for eight other variants. The rare exonic variant analysis showed associations betweenHMGCRandPOC5and 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.
Conclusion
A common variant intergenic toANKRD31andHMGCRwas associated with sepsis-associated ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed.
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