Genetic regulation of the vascular endothelial growth factor receptor 1 during sepsis and association with ARDS susceptibility

BackgroundAcute respiratory distress syndrome (ARDS) is associated with high mortality in Intensive Care Units (ICU). A previous genome-wide association study (GWAS) identified the vascular endothelial growth factor receptor 1 (VEGFR1) gene in ARDS risk. We performed a GWAS on soluble VEGFR1 (sVEGFR1) levels to identify protein quantitative trait loci (pQTLs) and genes of interest for ARDS. MethodsSerum samples (n=292) within the first 24 (T1), 72 hours (T2), and 7 days (T7) after sepsis diagnosis were collected while in the ICU. sVEGFR1 levels were measured and tested for association. We combined fine mapping, colocalisation and gene-set mapping analyses to prioritise genes and test low-frequency variation association with ARDS (n=822). We analysed the association of sVEGFR1 pQTLs with mortality and ARDS susceptibility using polygenic scores (PGS). Finally, the causality of VEGFR1 in ARDS was assessed using two-sample Mendelian randomisation (MR) analyses. ResultsWe found a pQTL for T2 sVEGFR1 levels at TCF20 (rs134871, p=4.66x10-8). Fine mapping prioritised rs762995 as a likely pathogenic variant and CYP2D6 as the most likely functional gene. The locus colocalised with eQTLs for TCF20 and CYP2D6. Low-frequency missense variation in TCF20 was associated with sepsis-associated ARDS susceptibility (p=3.0x10-3). sVEGFR1 levels PGS were associated with decreased ARDS susceptibility and mortality. MR analyses did not evidence causality. ConclusionsWe identified biologically relevant pQTLs of VEGFR1 levels during sepsis in TCF20 and identified CYP2D6 as the gene more biologically implicated. Low frequency missense variation in TCF20 and sVEGFR1 levels PGS models were associated with sepsis outcomes. What is already known on this topicAcute respiratory distress syndrome (ARDS) is an acute condition, characterised by respiratory failure, an acute inflammatory response and the development of non-cardiogenic oedema. There is a need for target pharmacological strategies and advances in the risk stratification methods that can improve patient management. What this study addsWe performed the first GWAS of sVEGFR1 levels in patients with sepsis. The integration of different complementary genomic approaches has allowed us to reveal a regulatory variant of sVEGFR1 during sepsis, suggesting a role in ARDS susceptibility and mortality. In exome-wide low-frequency variation analyses, we identified TCF20 as a novel gene of interest for ARDS. How this study might affect research, practice or policyThis study emphasises the value of proteogenomic approaches in improving our understanding of ARDS pathogenesis and detecting novel risk genes to advance patient risk stratification.