A functional variant in the 3ˈ-UTR of VEGF predicts the 90-day outcome of ischemic stroke in Chinese patients

Vascular endothelial growth factor (VEGF) plays critical roles in angiogenesis and vasculogenesis, which are associated with post-stroke functional recovery. However, the effects of the VEGFA polymorphisms on the outcome of ischemic stroke (IS) have been rarely reported. We therefore investigated the associations of +936C/T variant (rs3025039) with the susceptibilities and the 90-day outcomes from 494 IS patients and 337 healthy controls in Chinese population through the establishment of logistic multivariate regression model. Stroke severity at admission and outcome of 90 days were respectively assessed according to the National Institutes of Health Stroke Scale and the modified Rankin Scale. The analysis showed that there were no significant associations of the rs3025039 genotypes with the susceptibility (P = 0.229) and the severity (P = 0.734). However, when we divided the 308 IS patients into two groups according to the different outcomes, we found that the rs3025039 TC+TT genotype significantly increased the risk of poor recovery [adjusted odds ratio (OR), 1.99; 95% confidence interval (CI), 1.18–3.37]. Interestingly, we observed another 3ˈUTR variant, +1451C/T (rs3025040), exhibited strong linkage disequilibrium (r(2) = 1.0) with +936C/T and was located in a predicted microRNA-binding site. The rs3025040 T allele significantly decreased the luciferase activities in four cell lines, which indicated a potential disruption of the miRNA-mRNA interaction that would result in lower VEGF expression levels. Our data suggested that the +936C/T variants significantly increased the risk of poorer stroke outcome by affecting the bindings of miR-199a and miR-199b to VEGF mRNA at the rs30250340 polymorphic site.