Abstract 2389: Interaction of the Ile297 Variant of Vascular Endothelial Growth Factor Receptor-2 Gene and Homocysteine on the Risk of Stroke Recurrence for Patients with Hemorrhagic Stroke
Objectives- Stroke evolves depending on the accumulation of risk factors that exert abnormalities within the vessel wall, which leads to atherosclerotic lesions. Vascular endothelial growth factor (VEGF) plays a vital role in the process of angiogenesis and atherosclerosis via its receptors. In this study, we tested whether functional variants of VEGFR2 gene could increase risk for stroke and its recurrence, and their potential interactions with the established risk factors.
Methods and results- Total 1849 cases (43.9% cerebral athero-thrombosis, 28.7% lacunar infarction, and 27.4% intracerebral hemorrhage) and 1798 controls were recruited from 7 centers. Exonic variants Val297Ile and Gln472His in VEGFR2 gene were genotyped. Logistic regression analysis indicated that variants Ile297 and His472 conferred higher risk for intracerebral hemorrhage (OR = 2.25, 95% CI: 1.70 to 2.96; OR = 1.33, 95% CI: 1.03 to 1.73, respectively). Furthermore, radioligand binding assay showed that the binding affinity was increased by 2.49 folds in carriers with both risk alleles of Ile297 and His472, compared to the wild-type alleles (P < 0.001), which indicated possible stronger responses for VEGFR2 to its ligand VEGF within the vessel wall. To evaluate the impact of VEGFR2 gene and other established risk factors on stroke recurrence, all stroke patients were prospectively followed up for a median of 3.5 years. Of 1682 (91.1%) with follow-up data available, 356 (19.2%) cases had a recurrent stroke event. In the Cox regression model controlling for conventional risk factors, the Ile297 variant of VEGFR2 gene remained an independent predictor of stroke recurrence in patients with hemorrhagic subtype (hazard ratio [HR], 1.92; 95% CI, 1.29 to 2.85), so did the elevated homocysteine level (the top 75th percentile of plasma homocysteine as the cutoff value) (HR, 1.93; 95% CI: 1.28 –2.91). In the risk stratification analysis, there was a markedly increased stroke recurrence at hyperhomocysteinemia for hemorrhagic patients bearing the risk variant Ile297 (HR, 3.87; 95% CI, 2.29 to 6.59).
Conclusions- These data indicate that the Ile297 variant of VEGFR2 gene and hyperhomocysteinemia synergistically confer higher risks for stroke recurrence in patients with hemorrhagic stroke.