VEGFA and VEGFR-1 gene polymorphisms and susceptibility to sepsis and organ dysfunction

Abstract

Abstract Vascular endothelial growth factor (VEGF) and its receptors regulate vascular permeability and inflammation, processes central to sepsis pathophysiology. Genetic variation in VEGF pathways may influence host response, but evidence in sepsis remains limited and inconsistent. This study aimed to investigate associations between VEGFA and VEGFR-1 polymorphisms and sepsis susceptibility in critically ill adults. Four single-nucleotide polymorphisms (SNPs) were genotyped from whole blood samples: VEGFA rs833061, rs2010963, rs699947, and VEGFR-1 rs9508032. Logistic regression under multiple genetic models was applied, adjusting for age, sex, acute organ dysfunctions and comorbidities. Analyses were stratified by sex and clinical subgroups. Bonferroni correction addressed multiple testing, and haplotype analyses were conducted. The VEGFR-1 rs9508032 variant was significantly associated with sepsis in dominant and overdominant models after Bonferroni correction. VEGFA rs2010963 showed nominal associations across dominant and overdominant models. Other SNPs demonstrated nominal associations in subgroup analyses but did not remain significant after multiple testing corrections. Exploratory sex-stratified analyses were stronger among men. Haplotypes combining VEGFA SNPs displayed consistent, but non-significant trends after correction. The VEGFR-1 rs9508032 polymorphism may be a potential contributor of sepsis susceptibility, supporting a role for VEGF signalling in sepsis pathophysiology. While exploratory findings require validation in larger, multi-ethnic studies, these results suggest that VEGF pathway variants could contribute to personalised risk stratification in critical care.