Angiopoietin-1 is a vascular strengthening factor during vascular development and a protective factor for pathological vascular
inflammation and leakage. Brain vascular leaking and
inflammation are two important
pathological processes of
stroke; therefore, we hypothesized that variants of the
microRNA-binding site in
angiopoietin-1 would affect its expression and confer a risk of
stroke. To test our hypothesis, a predicted
microRNA-binding site was found in the 3'-UTR of
angiopoietin-1 using bioinformatics; variant rs2507800 was identified to be located in the miR-211-binding site of
angiopoietin-1. Secondly, the effects of the identified variant on
angiopoietin-1 translation were assessed using a
luciferase reporter assay and ELISA. We found that the A allele of rs2507800 suppressed
angiopoietin-1 translation by facilitating miR-211 binding, but not the T allele. Subjects carrying the TT genotype had higher plasma
angiopoietin-1 levels than those with the A allele. Finally, the association of the variant with
stroke was tested in 438
stroke patients and 890 controls, and replicated in an independent population of 1791
stroke patients and 1843 controls. The TT genotype resulted in a significant reduction in overall
stroke risk {OR, 0.51 [95% confidence interval (CI), 0.36-0.74], P = 0.0003},
ischemic stroke [OR, 0.56 (95% CI, 0.36-0.85), P = 0.007] and
hemorrhagic stroke [OR, 0.46 (95% CI, 0.26-0.80), P = 0.007]. These results were confirmed in an independent study. Our results provide evidence that the TT genotype (rs2507800) in the 3'-UTR of
angiopoietin-1 might reduce the risk of
stroke by interfering with miR-211 binding.