title: Association of renin-angiotensin system genetic polymorphisms and aneurysmal subarachnoid hemorrhage.
abstract: 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.
authors.affiliation: 1Beth Israel Deaconess Medical Center.|2Harvard Medical School, Boston, Massachusetts.|3Children's of Alabama.|4Department of Neurosurgery, University of Alabama at Birmingham, Alabama.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Griessenauer
authors.affiliation: 3Children's of Alabama.
authors.forename: R Shane
authors.initials: RS
authors.lastname: Tubbs
authors.affiliation: 4Department of Neurosurgery, University of Alabama at Birmingham, Alabama.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Foreman
authors.affiliation: 2Harvard Medical School, Boston, Massachusetts.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Chua
authors.affiliation: 5Department of Neurosciences.
authors.forename: Nilesh A
authors.initials: NA
authors.lastname: Vyas
authors.affiliation: 5Department of Neurosciences.|6Department of Molecular Neuroscience, George Mason University, Fairfax, Virginia.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lipsky
authors.affiliation: 6Department of Molecular Neuroscience, George Mason University, Fairfax, Virginia.
authors.forename: Mingkuan
authors.initials: M
authors.lastname: Lin
authors.affiliation: 7Inova Translational Medicine Institute, Inova Health System, Falls Church; and.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Iyer
authors.affiliation: 7Inova Translational Medicine Institute, Inova Health System, Falls Church; and.
authors.forename: Rishikesh
authors.initials: R
authors.lastname: Haridas
authors.affiliation: 4Department of Neurosurgery, University of Alabama at Birmingham, Alabama.|5Department of Neurosciences.
authors.forename: Beverly C
authors.initials: BC
authors.lastname: Walters
authors.affiliation: 6Department of Molecular Neuroscience, George Mason University, Fairfax, Virginia.
authors.forename: Salman
authors.initials: S
authors.lastname: Chaudry
authors.affiliation: 6Department of Molecular Neuroscience, George Mason University, Fairfax, Virginia.
authors.forename: Aisana
authors.initials: A
authors.lastname: Malieva
authors.affiliation: 6Department of Molecular Neuroscience, George Mason University, Fairfax, Virginia.
authors.forename: Samantha
authors.initials: S
authors.lastname: Wilkins
authors.affiliation: 4Department of Neurosurgery, University of Alabama at Birmingham, Alabama.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Harrigan
authors.affiliation: 4Department of Neurosurgery, University of Alabama at Birmingham, Alabama.
authors.forename: Winfield S
authors.initials: WS
authors.lastname: Fisher
authors.affiliation: 3Children's of Alabama.
authors.forename: Mohammadali M
authors.initials: MM
authors.lastname: Shoja
mesh_terms: D000808:Angiotensinogen / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D002532:Intracranial Aneurysm / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000201:enzymology / Q000235:genetics*
chemical_list: C534931:AGT protein, human; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A
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; HWE = Hardy-Weinberg equilibrium; I/D = insertion/deletion; MAF = minor allele frequency; PCR = polymerase chain reaction; RAS = renin-angiotensin system; SNP = single-nucleotide polymorphism; VSMC = vascular smooth-muscle cell; aSAH = aneurysmal subarachnoid hemorrhage; angiotensin; cerebral aneurysm; renin; rupture; subarachnoid hemorrhage; vascular disorders