Endothelial Nitric Oxide Synthase Polymorphism (−786T→C) and Increased Risk of Angiographic Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Abstract

Background and Purpose— Vasospasm after aneurysmal subarachnoid hemorrhage (SAH) remains a leading cause of death and disability after aneurysm rupture. Decreased availability of nitric oxide (NO) may be crucial in its pathogenesis. We hypothesized that endothelial NO synthase ( eNOS ) polymorphisms may determine susceptibility to vasospasm in SAH patients. Methods— We conducted a prospective cohort study of SAH patients and determined vasospasm by cerebral angiography. We genotyped 3 eNOS polymorphisms: an intron 4 variable-number tandem-repeat, a promoter single-nucleotide polymorphism (−786T→C SNP), and a coding SNP in exon 7 (894G→T encoding E298D). Using multivariable logistic regression, we quantified the association of eNOS polymorphisms in patients with vasospasm confirmed by cerebral angiography. Results— For the eNOS promoter −786T→C SNP, the presence of the CC genotype compared with any T genotype ( CT or TT ) was associated with increased odds of vasospasm (odds ratio=2.97, 95% CI=1.32 to 6.67, P =0.008). No association with vasospasm was observed for the eNOS 894G→T or variable-number tandem-repeat polymorphisms. Conclusions— These findings suggest that genetic variation influencing NO regulation contributes to the risk of angiographic vasospasm in patients with SAH. The specific role of the promoter SNP (−786T→C) may determine the effect of NO regulated by this pathway, distinct from other known eNOS polymorphisms.