Potential Therapeutic Target for ARDS Is Identified
Vascular endothelial growth factor receptor 1 (VEGFR-1) may be a potential therapeutic target for patients with acute respiratory distress syndrome (ARDS), according to findings of a new study.
The findings also support a role for the vascular endothelial growth factor signaling pathway in ARDS pathogenesis.
These determinations come after the researchers found that a common variant within the Fms-related tyrosine kinase 1 (FLT1) gene is associated with sepsis-associated ARDS.
The genome-wide association study comprised 1935 European individuals with sepsis-associated ARDS and without ARDS.
The discovery stage included 672 patients who had been admitted into a network of intensive care units in Spain between January 2002 and January 2017. The replication stage included 1345 individuals from 2 independent datasets from the MESSI cohort study, as well as from the VISEP and MAXSEP trials of the SepNet study.
To identify association signals, the researchers conducted a meta-analysis of the results from the discovery and replication stages. To assess the functionality of associated variants, the researchers then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays.
“We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR], 0.61; 95% CI 0.41–0.91, p=5.18 × 10−8) located within the FLT1 gene, which encodes VEGFR-1,” the researchers wrote.
The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter. Promoter activity was further reduced by alleles with protective effects in ARDS.
The association of vascular endothelial growth factor A was validated via a literature mining of all previously described ARDS genes.
—Colleen Murphy
Reference:
Guillen-Guio B, Lorenzo-Salazar JM, Ma SF, et al. Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: a genome-wide association study. Lancet Respir Med. 2020;8(3):258-266. doi:10.1016/S2213-2600(19)30368-6