Abstract 2387: Vascular Endothelial Growth Factor Receptor-2 Gene Haplotype (TAT, -604/+1192/+1719) is Associated with Increased Risk of Hemorrhagic Stroke: A Multicenter Case-control Study
Objectives- Vascular endothelial growth factor (VEGF), a potent endothelial cell mitogen and vascular permeability-enhancing factor, plays a vital role in the process of angiogenesis and atherosclerosis. Disruption of VEGF tyrosine-kinase receptors results in some angiogenesis-related diseases. SNPs -460T/C, -116G/A, and +405G/C in VEGF gene have been reported to be associated with VEGF expression. SNPs +1192G/A and +1719A/T of VEGFR2 gene result in change of nonsynonymous amino acid at V297I and Q472H respectively. These variants are located in the Ig-like domain of VEGFR2 important for ligand binding. SNP -604T/C, located at the promoter region, may influence VEGFR2 expression. In this study, we tested whether these variants could increase the risk of stroke.
Methods- Total 1849 patients with stroke (43.9% cerebral atherothrombosis, 28.7% lacunar infarction, and 27.4% intracerebral hemorrhage) and 1798 controls were recruited from 7 centers. Polymorphisms of VEGF and VEGFR2 were genotyped by PCR-RFLP assays and confirmed by sequencing.
Results- Logistic regression analysis indicated that -604C allele in the VEGFR2 promoter region was associated with decreased risk for atherothrombotic stroke (OR = 0.78, 95% CI: 0.65– 0.95), furthermore, dual-luciferase assay revealed that -604C significantly decreased basal transcriptional activity by 2.93 folds compared to the wild-type T allele (P < 0.001) when transfected into HUVECs. Alleles +1192A and +1719T of VEGFR2 conferred higher risk for intracerebral hemorrhage. Haplotypes analysis (-604/+1192/+1719) showed that C/G/T haplotype provided a protective effect against atherothrombotic stroke (OR = 0.59, 95% CI: 0.43 to 0.82), and T/A/T haplotype, a greater risk for hemorrhagic stroke (OR = 3.18, 95%CI: 1.79 to 5.67). The radioligand binding assay showed that the binding affinity of VEGF to VEGFR2 was increased by 2.49 folds in carriers with both risk alleles of +1192A and +1719T, compared to the wild-type alleles (P < 0.001). All VEGF markers were not associated with stroke, and no interaction was found between VEGF and VEGFR2.
Conclusions- Our functional and genetic findings for the first time indicate that VEGFR2 gene variants are associated with stroke, particularly intracerebral hemorrhage.