Association of renin-angiotensin system genetic polymorphisms and aneurysmal subarachnoid hemorrhage.

OBJECTIVE Renin-angiotensin system (RAS) genetic polymorphisms are thought to play a role in cerebral aneurysm formation and rupture. The Cerebral Aneurysm Renin-Angiotensin System (CARAS) study prospectively evaluated common RAS polymorphisms and their relation to aneurysmal subarachnoid hemorrhage (aSAH). METHODS The CARAS study prospectively enrolled aSAH patients and controls at 2 academic centers in the United States. A blood sample was obtained from all patients for genetic evaluation and measurement of plasma angiotensin-converting enzyme (ACE) concentration. Common RAS polymorphisms were detected using 5' exonuclease (TaqMan) genotyping assays and restriction fragment length polymorphism analysis. RESULTS Two hundred forty-eight patients were screened, and 149 aSAH patients and 50 controls were available for analysis. There was a recessive effect of the C allele of the angiotensinogen ( AGT) C/T single-nucleotide polymorphism (SNP) (OR 1.94, 95% CI 0.912-4.12, p = 0.0853) and a dominant effect of the G allele of the angiotensin II receptor Type 2 ( AT2) G/A SNP (OR 2.11, 95% CI 0.972-4.57, p = 0.0590) on aSAH that did not reach statistical significance after adjustment for potential confounders. The ACE level was significantly lower in aSAH patients with the II genotype (17.6 ± 8.0 U/L) as compared with the ID (22.5 ± 12.1 U/L) and DD genotypes (26.6 ± 14.2 U/L) (p = 0.0195). CONCLUSIONS The AGT C/T and AT2 G/A polymorphisms were not significantly associated with aSAH after controlling for potential confounders. However, a strong trend was identified for a dominant effect of the G allele of the AT2 G/A SNP. Downregulation of the local RAS may contribute to the formation of cerebral aneurysms and subsequent presentation with aSAH. Further studies are required to elucidate the relevant pathophysiology and its potential implication in treatment of patients with aSAH.

Associations of renin-angiotensin system genetic polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage.

OBJECTIVE Renin-angiotensin system (RAS) genetic polymorphisms are thought to play a role in cerebral aneurysm formation and rupture. The Cerebral Aneurysm Renin Angiotensin System (CARAS) study prospectively evaluated associations of common RAS polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage (aSAH). METHODS The CARAS study prospectively enrolled aSAH patients at 2 academic centers in the United States. A blood sample was obtained from all patients for genetic evaluation and measurement of plasma angiotensin converting enzyme (ACE) concentration. Common RAS polymorphisms were detected using 5'exonuclease genotyping assays and pyrosequencing. Analysis of associations of RAS polymorphisms and clinical course after aSAH were performed. RESULTS A total of 166 patients were screened, and 149 aSAH patients were included for analysis. A recessive effect of allele I (insertion) of the ACE I/D (insertion/deletion) polymorphism was identified for Hunt and Hess grade in all patients (OR 2.76, 95% CI 1.17-6.50; p = 0.0206) with subsequent poor functional outcome. There was a similar effect on delayed cerebral ischemia (DCI) in patients 55 years or younger (OR 3.63, 95% CI 1.04-12.7; p = 0.0439). In patients older than 55 years, there was a recessive effect of allele A of the angiotensin II receptor Type 2 (AT2) A/C single nucleotide polymorphism (SNP) on DCI (OR 4.70, 95% CI 1.43-15.4; p = 0.0111). CONCLUSIONS Both the ACE I/D polymorphism and the AT2 A/C single nucleotide polymorphism were associated with an age-dependent risk of delayed cerebral ischemia, whereas only the ACE I/D polymorphism was associated with poor clinical grade at presentation. Further studies are required to elucidate the relevant pathophysiology and its potential implication in the treatment of patients with aSAH.