Protein-based genomic analysis for the identification of risk loci associated with acute respiratory distress syndrome

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening lung condition that requires admission to an intensive care unit (ICU). Sepsis is one of the leading causes of ARDS and understanding protein regulation during sepsis could reveal key mechanisms that predispose patients to ARDS. We performed genome-wide association studies (GWAS) on ARDS biomarkers levels to identify protein quantitative trait loci (pQTLs) and genes which could be associated with ARDS risk. MethodsGWAS were performed in 209 patients with sepsis from the GEN-SEP cohort to determine the association of imputed genotypes with 10 serum biomarker levels relevant to ARDS. Measurements were obtained by ELISA within the first 24 hours (T1), 48-72 hours (T2), and 7 days (T7) after the diagnosis of sepsis. We conducted a multi-trait analysis to aggregate the GWAS results for each biomarker at three time points. We prioritized genes in the significant loci (p<5x10-8) and evaluated the association between rare variants and ARDS in whole-exome sequencing data from 272 patients with sepsis-associated ARDS and 550 sepsis controls from GEN-SEP. We analyzed the aggregated association of pQTLs with ICU mortality, multiple organ failure, and ARDS risk using polygenic scores (PGS) in independent patients (n=621) from GEN-SEP. ResultsWe identified 27 significant independent loci and prioritized 56 genes. Seven of these were previously associated with respiratory infections and diseases (LINGO2, MC4R, MCTP1, NUAK1, PIEZO2, PTPRD, and TMEMc5). Defects in another prioritized gene, FOXN1, cause an inborn error of immunity. Rare variants in PTPRD, which was previously involved in COVID-19 severity and pulmonary hypertension, were significantly associated with ARDS (p=3.11x10-4). PGS of PAI-1 levels was significantly associated with ICU mortality. ConclusionsWe prioritized genes of interest governing ARDS biomarker levels and identified PTPRD as a novel gene associated with ARDS risk. In addition, we demonstrate the value of biomarker PGS for predicting sepsis mortality. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/26344107v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1654886org.highwire.dtl.DTLVardef@7c8865org.highwire.dtl.DTLVardef@1dea651org.highwire.dtl.DTLVardef@791901_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG