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.
Keywords: ACE = angiotensin-converting enzyme; AGT = angiotensinogen; AT1 = angiotensin II receptor Type 1; AT2 = angiotensin II receptor Type 2; CARAS = Cerebral Aneurysm Renin Angiotensin System; CTA = CT angiography; DCI = delayed cerebral ischemia; DSA = digital subtraction angiography; FDR = false discovery rate; HWE = Hardy-Weinberg equilibrium; PCR = polymerase chain reaction; RAS = renin-angiotensin system; SNP = single nucleotide polymorphism; VSMC = vascular smooth muscle cell; aSAH = aneurysmal subarachnoid hemorrhage; aneurysm; angiotensin; eNOS = endothelial nitric oxide synthase; mRS = modified Rankin Scale; renin; rupture; subarachnoid hemorrhage; vascular disorders.