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on February 28, 2008

Stroke. 2008
Published online before print February 28, 2008, doi: 10.1161/STROKEAHA.107.496596
A more recent version of this article appeared on April 1, 2008
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Right arrow Endothelium/vascular type/nitric oxide
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Submitted on June 13, 2007
Revised on August 1, 2007
Accepted on August 22, 2007

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

Nerissa U. Ko MD*; Pam Rajendran MD; Helen Kim PhD; Martin Rutkowski BA; Ludmila Pawlikowska PhD; Pui-Yan Kwok MD, PhD; Randall T. Higashida MD; Michael T. Lawton MD; Wade S. Smith MD, PhD; Jonathan G. Zaroff MD; and William L. Young MD

From the Departments of Neurology (N.U.K., P.R., M.R., W.S.S., W.L.Y.), Radiology (R.T.H.), Neurological Surgery (M.T.L., W.L.Y.), Anesthesia and Perioperative Care/Center for Cerebrovascular Research (H.K., L.P., W.L.Y.); and the Cardiovascular Research Institute (P.-Y.K.), University of California, San Francisco; Division of Research, Kaiser Permanente Medical Care Program (J.G.Z.), Oakland, Calif.

* To whom correspondence should be addressed. E-mail: kon{at}ucsfmedctr.org.

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.
Key words: endothelial nitric oxide • genetics • subarachnoid hemorrhage • vasospasm






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