Update on genetic evidence for rupture-prone compared with rupture-resistant intracranial saccular aneurysms.

OBJECT: Anecdotal evidence exists for at least two subpopulations of intracranial saccular aneurysms; those that form rapidly and rupture when small and those that enlarge slowly and are particularly prone to rupture when they are 10 mm or more in diameter. The goal in this study was to determine if there was genetic evidence to support the classification of intracranial saccular aneurysms as 'rupture-prone' or 'rupture-resistant' lesions. METHODS: The authors prospectively obtained and analyzed clinical and genetic data in a cohort of 197 individuals composed of 58 patients with ruptured intracranial saccular aneurysms, 49 with unruptured aneurysms, and 90 healthy community volunteers. Based on recent studies supporting an increasingly relevant role for the critical vasomodulatory protein endothelial nitric oxide synthase (eNOS) in aneurysm pathobiology, the authors assayed blood from all 197 participants to determine and compare their eNOS genotypes. The eNOS gene intron 4 27-base pair variable-number tandem-repeat polymorphism was significantly overrepresented in persons with ruptured intracranial saccular aneurysms compared with community volunteers (p < 0.002). When comparing eNOS genotypes among patients with ruptured or unruptured aneurysms, an approximately 10-fold increase in the odds of presenting with brain aneurysm rupture was found among individuals with multiple variant eNOS alleles (p = 0.004). CONCLUSIONS: Uniquely, the authors have identified a set of eNOS gene variations whose presence indicates patients with intracranial saccular aneurysms that are more prone to rupture. The authors conclude that if these findings are reproducible in the setting of a large multicenter study, then in addition to known anatomical factors, a rapid and costeffective genetic screening tool will become available to clinicians as an aid to predicting rupture risks in patients presenting with unruptured intracranial aneurysms.