Endothelial Nitric Oxide Synthase T-786C Single Nucleotide Polymorphism: A Putative Genetic Marker Differentiating Small Versus Large Ruptured Intracranial Aneurysms

Background and Purpose - Anecdotal evidence exists for at least 2 subpopulations of intracranial saccular aneurysms, namely, those that may form rapidly and rupture when small versus those that enlarge slowly and may rupture particularly when ≥10 mm in diameter. We sought to determine whether the endothelial nitric oxide synthase (eNOS) T-786C single nucleotide polymorphism (SNP), implicated in cardiovascular disease susceptibility, could facilitate differentiation between small (≤5 mm) versus large (≥10 mm) ruptured aneurysms. Methods - In accordance with institutional guidelines, clinical data were recorded prospectively and genomic DNA was isolated from blood samples obtained from 52 aneurysmal subarachnoid hemorrhage (SAH) patients (cases) and 90 randomly selected controls. Samples were assayed for eNOS gene promoter T-786C SNP with the use of gene microarray technology. Statistical analyses included multiple logistic regression. Results - Although there was no difference in genotype distributions between cases and controls, all 13 patients with large aneurysms were (T/C) heterozygous for the polymorphism, while 9 of 22 patients (41%) with small aneurysms were (T/T or C/C) homozygous (P=0.01). The mean (±SD) ruptured aneurysm diameter among all heterozygotes (8.5±5.2 mm) was significantly greater than that for C/C (6.0±2.3 mm) or T/T (4.7±1.8 mm) homozygotes (P=0.04). With the use of multivariate analysis, heterozygosity remained significantly associated with aneurysm size ≥10 mm (P=0.03). Conclusions - The eNOS T-786C SNP distinguishes genetically between small and large ruptured aneurysms. Although not predictive of SAH in the population at large, our data suggest that among persons with known intracranial aneurysms, eNOS T-786C genotype may be a factor influencing the size at which an aneurysm ruptures, a finding that should be taken into consideration along with other anatomic features of the aneurysm.