The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture

OBJECT: It is becoming apparent that the presence of certain genetic variations (polymorphisms) may increase the individual's susceptibility to cardiovascular diseases, even in the absence of a family history. We hypothesized that brain aneurysms more prone to rupture may be identified on the basis of an individual's genotype for endothelial nitric oxide synthase (eNOS), a critical vasomodulatory protein found to be increasingly relevant to the pathobiology of aneurysms. METHODS: Patients' clinical data were recorded prospectively. Genomic DNA was isolated from blood samples obtained from individuals presenting consecutively to the Mayo Clinic with ruptured (58 patients) or unruptured (49 patients) intracranial saccular aneurysms. Using polymerase chain reaction and gene microarray technology, the following eNOS genetic polymorphisms were studied: intron-4 27-base pair variable number of tandem repeats (27 VNTR); promoter single nucleotide polymorphism (T-786C SNP); and exon-7 SNP (G894T SNP). Both groups of patients had similar demographic and clinical characteristics. For all three polymorphisms, variant alleles (p < or = 0.003) and their corresponding genotypes (p < or = 0.006) were found two to four times more frequently in patients with ruptured aneurysms than in patients with unruptured aneurysms. Strikingly, the odds ratio for presenting with a ruptured brain aneurysm among individuals demonstrating the copresence of all three variant alleles was 11.4 (95% confidence interval 1.7-75.9, p = 0.004). CONCLUSIONS: The authors have uniquely identified a set of tandem eNOS gene variations whose presence can be used to identify patients with aneurysms likely to rupture. We believe that if this finding is reproducible in a large multicenter study, in addition to known anatomical factors a rapid and cost-effective screening tool will become available to clinicians as a genetic aid to predict the risks of rupture in patients presenting with unruptured intracranial aneurysms.