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

Christoph J. Griessenauer, R. Shane Tubbs, Paul M. Foreman, Michelle H. Chua, Nilesh A. Vyas, Robert H. Lipsky, Mingkuan Lin, Ramaswamy Iyer, Rishikesh Haridas, Beverly C. Walters, Salman Chaudry, Aisana Malieva, Samantha Wilkins, Mark R. Harrigan, Winfield S. Fisher, Mohammadali Mohajel Shoja

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1585-1597
Number of pages13
JournalJournal of Neurosurgery
Volume126
Issue number5
DOIs
StatePublished - May 1 2017
Externally publishedYes

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Genetic Polymorphisms
Subarachnoid Hemorrhage
Renin-Angiotensin System
Peptidyl-Dipeptidase A
Intracranial Aneurysm
Brain Ischemia
Single Nucleotide Polymorphism
Alleles
Angiotensin Type 2 Receptor
Rupture

Keywords

  • Aneurysm
  • Angiotensin
  • Renin
  • Rupture
  • Subarachnoid hemorrhage
  • Vascular disorders

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Griessenauer, C. J., Tubbs, R. S., Foreman, P. M., Chua, M. H., Vyas, N. A., Lipsky, R. H., ... Mohajel Shoja, M. (2017). Associations of renin-angiotensin system genetic polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery, 126(5), 1585-1597. https://doi.org/10.3171/2016.4.JNS16409

Associations of renin-angiotensin system genetic polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage. / Griessenauer, Christoph J.; Tubbs, R. Shane; Foreman, Paul M.; Chua, Michelle H.; Vyas, Nilesh A.; Lipsky, Robert H.; Lin, Mingkuan; Iyer, Ramaswamy; Haridas, Rishikesh; Walters, Beverly C.; Chaudry, Salman; Malieva, Aisana; Wilkins, Samantha; Harrigan, Mark R.; Fisher, Winfield S.; Mohajel Shoja, Mohammadali.

In: Journal of Neurosurgery, Vol. 126, No. 5, 01.05.2017, p. 1585-1597.

Research output: Contribution to journalArticle

Griessenauer, CJ, Tubbs, RS, Foreman, PM, Chua, MH, Vyas, NA, Lipsky, RH, Lin, M, Iyer, R, Haridas, R, Walters, BC, Chaudry, S, Malieva, A, Wilkins, S, Harrigan, MR, Fisher, WS & Mohajel Shoja, M 2017, 'Associations of renin-angiotensin system genetic polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage', Journal of Neurosurgery, vol. 126, no. 5, pp. 1585-1597. https://doi.org/10.3171/2016.4.JNS16409
Griessenauer, Christoph J. ; Tubbs, R. Shane ; Foreman, Paul M. ; Chua, Michelle H. ; Vyas, Nilesh A. ; Lipsky, Robert H. ; Lin, Mingkuan ; Iyer, Ramaswamy ; Haridas, Rishikesh ; Walters, Beverly C. ; Chaudry, Salman ; Malieva, Aisana ; Wilkins, Samantha ; Harrigan, Mark R. ; Fisher, Winfield S. ; Mohajel Shoja, Mohammadali. / Associations of renin-angiotensin system genetic polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage. In: Journal of Neurosurgery. 2017 ; Vol. 126, No. 5. pp. 1585-1597.
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AU - Griessenauer, Christoph J.

AU - Tubbs, R. Shane

AU - Foreman, Paul M.

AU - Chua, Michelle H.

AU - Vyas, Nilesh A.

AU - Lipsky, Robert H.

AU - Lin, Mingkuan

AU - Iyer, Ramaswamy

AU - Haridas, Rishikesh

AU - Walters, Beverly C.

AU - Chaudry, Salman

AU - Malieva, Aisana

AU - Wilkins, Samantha

AU - Harrigan, Mark R.

AU - Fisher, Winfield S.

AU - Mohajel Shoja, Mohammadali

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N2 - 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.

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