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

Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis

“…Both the recessive AGTR2 A/C allele SNP (OR 4.70, 95% CI 1.43-15.4) and the recessive effect of the insertion allele of the ACE rs4340 insertion-deletion polymorphism (also known as rs4646994; OR 3.63, 95% CI 1.04-12.7) were linked to an increased risk of symptomatic cerebral vasospasm. 47 Similarly, another study demonstrated a link between impaired reactivity to CO2, measured using TCD ultrasonography, and the angiotensinogen (AGT) rs699 CC genotype (P=0.00028) in healthy elderly volunteers. 49 In addition, research in patients with TBI supports the link between ACE rs7221780 (OR 2.67, 95% CI: 1.25 -5.72) and rs8066276 (OR 3.82, 95% CI: 1.80 -8.13) and global patient outcome, with the minor alleles linked to a worse 6-month Glasgow Outcome Scale (GOS) score.…”

“…Mutations in genes encoding angiotensin-converting enzyme (ACE) and the angiotensin II receptor have been linked to the development of delayed ischaemic neurological deficits in subarachnoid haemorrhage. 47,48 The type 2 angiotensin II receptor (AGTR2) A/C SNP (rs11091046) has been linked to the development of aneurysmal subarachnoid haemorrhage. Both the recessive AGTR2 A/C allele SNP (OR 4.70, 95% CI 1.43-15.4) and the recessive effect of the insertion allele of the ACE rs4340 insertion-deletion polymorphism (also known as rs4646994; OR 3.63, 95% CI 1.04-12.7) were linked to an increased risk of symptomatic cerebral vasospasm.…”

Associations between endothelin polymorphisms and aneurysmal subarachnoid hemorrhage, clinical vasospasm, delayed cerebral ischemia, and functional outcome

“…Blood samples from all patients and controls enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study were used for genetic evaluation; much of the method has previously been reported. [5][6][7]9,10 In the CARAS study, the diagnosis of aSAH was established on the basis of the admission CT scan or xanthochromia of CSF. A ruptured aneurysm as the source of hemorrhage was confirmed by CT angiography (CTA) or digital subtraction angiography (DSA).…”

A Review of Genetic Polymorphisms and Susceptibilities to Complications after Aneurysmal Subarachnoid Hemorrhage

“…In some laboratory studies, DCI improved after the administration of isoflurane as a result of the increase in eNOS expression [ 26 , 27 ]. The importance that NO plays in the effects of SAH has encouraged studies that seek to establish a relationship between the SNPs of eNOS , and the origin and complications of aSAHs [ 23 , 28 , 29 , 30 , 31 , 32 , 33 ].…”