P107 Vascular endothelial growth factor and acute respiratory distress syndrome: a Mendelian randomisation study

Abstract

Introduction Acute respiratory distress syndrome (ARDS) is a severe inflammatory lung disorder mainly caused by sepsis resulting from both pulmonary and non-pulmonary infections. ARDS is characterised by rapid onset of acute respiratory failure and has a hospital mortality of about 40%. A previous genome-wide association study (GWAS) of sepsis-associated ARDS revealed an association between genes in the vascular endothelial growth factor signalling pathway (VEGFA and VEGFR1) and ARDS susceptibility.1

Objective Assess the causal relationship between VEGFA and VEGFR1 circulating levels and ARDS risk.

Methods We used two-sample bidirectional Mendelian randomisation (MR) to test the causal effect of VEGFA and VEGFR1 serum levels on ARDS, and of ARDS on VEGFA and VEGFR1 serum levels. We used genetic variants from GWAS of both VEGFA and VEGFR1 serum levels (UK Biobank, N=46,836) and of sepsis-associated ARDS (N= 274 ARDS cases and 316 controls with sepsis) as instrumental variables. We used the inverse variance-weighted (IVW) method to test causality and performed sensitivity analyses with five additional methods. We evaluated presence of pleiotropy and outliers. MR-RAPS was used to test weak instrumental variables (p<0.05).

Results No significant causal effect on ARDS risk was observed for either VEGFA (pIVW=0.992) or VEGFR1 (pIVW=0.924) serum levels based on our findings. Similarly, we found no indication that ARDS has a causal effect on either VEGFA (pIVW=0.487) or VEGFR1 (pIVW=0.168) serum levels. Sensitivity analyses supported these results.

Conclusions Our results do not provide evidence for a causal link between serum levels of VEGFA or VEGFR1 and susceptibility to sepsis-associated ARDS. Further analyses are required to explore the impact of VEGF regulation during the acute phase on the development of ARDS.