on June 11, 2009
Published online before print June 11, 2009, doi: 10.1161/STROKEAHA.109.554394
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Submitted on April 1, 2009
From the Sino-German Laboratory for Molecular Medicine and Key Laboratory for Clinical Cardiovascular Genetics (W.Z., K.S., Y.W., Y.Z., J.C., R.H.), Hypertension Division, Cardiovascular Institute and FuWai Hospital, Chinese Academy of Medical Sciences, Beijing, China; Tongji Hospital (D.W.), Huazhong University of Science and Technology, Wuhan, China; Center for Human Genomics (J.X.), Wake Forest University School of Medicine, Winston-Salem, NC; and the Department of Nutrition and Epidemiology (F.B.H.), Harvard School of Public Health and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. * To whom correspondence should be addressed. E-mail: huirutai{at}sglab.org.
Background and Purpose—Dysregulation of vessel wall formation, growth, and maintenance may confer susceptibility of stroke. Methods—We tested the hypothesis that variants in 2 genes encoding vascular endothelial growth factor and vascular endothelial growth factor receptor-2 are associated with susceptibility to stroke and its recurrence in a Chinese case–control study comprising 1849 patients with stroke and 1798 control subjects and replicated the investigation in an independent study comprising 327 cases and 327 control subjects. The correlation of variants with carotid artery intima media thickness was examined in 1123 healthy individuals. Results—Compared with their corresponding wild-type genotypes, one coding variant, rs2305948 (Val297Ile), in the vascular endothelial growth factor receptor-2 gene was associated with increased susceptibility to intracerebral hemorrhage (additive model: OR, 2.06; 95% CI, 1.64 to 2.59; P=7.6x10-10; dominant model: OR, 2.20; 95% CI, 1.70 to 2.84; P=1.5x10-9), a promoter variant rs2071559 (-604T>C) in the gene was associated with reduced susceptibility to atherothrombotic stroke (additive model: OR, 0.82; 95% CI, 0.71 to 0.93; P=0.003; dominant model: OR, 0.78; 95% CI, 0.65 to 0.92; P=0.004) and was reversely correlated with carotid artery intima media thickness (P=2.8x10-5). Replication in the second study yielded similar results. During a median 4.5 years of follow-up for the first stroke population, 355 recurrent strokes were documented. Subjects carrying 297Ile had a higher risk for stroke recurrence (relative risk, 1.40; 95% CI, 1.12 to 1.75; P=0.003), and those with -604C had a lower risk for recurrence (relative risk, 0.71; 95% CI, 0.58 to 0.89; P=0.002) than their wild-type carriers. Conclusions—The vascular endothelial growth factor receptor-2 gene variants may serve as novel genetic markers for the risk of stroke and its recurrence.
Accepted on May 5, 2009
VEGF Receptor-2 Variants Are Associated With Susceptibility to Stroke and Recurrence
Weili Zhang MD, PhD;
Key words: follow-up studies • genetics • risk factors • stroke • vascular endothelial growth factor