Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage: Clinical article

Bartosz T. Grobelny, Andrew F. Ducruet, Peter A. Derosa, Ivan S. Kotchetkov, Brad E. Zacharia, Zachary L. Hickman, Luis Fernandez, Reshma Narula, Jan Claassen, Kiwon Lee, Neeraj Badjatia, Stephan A. Mayer, E. Sander Connolly

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Object. Cystathionine β-synthase (CBS) is an enzyme that metabolizes homocysteine to form H2S in the brain. Hydrogen sulfide functions as a vasodilator as well as a regulator of neuronal ion channels and multiple intracellular signaling pathways. Given the myriad effects of H2S, the authors hypothesized that patients possessing gain-of-function polymorphisms of the CBS gene will experience a decreased incidence of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). Methods. Patients were enrolled in a prospective observational database of aSAH outcomes. DNA was extracted from buccal swabs and sequenced for 3 functional polymorphisms of the CBS gene (699C→T, 844ins68, and 1080C→T) by polymerase chain reaction. Serum homocysteine levels (mmol/L) were assayed. Multivariate analysis was used to determine the relationship between CBS genotype and occurrence of both angiographic vasospasm and DCI. Results. There were 87 patients included in the study. None of the polymorphisms investigated were significantly associated with the incidence of angiographic vasospasm. However, after controlling for admission hypertension, patients with the gain-of-function 844 WT/ins genotypes were less likely to experience DCI relative to those with the 844 WT/WT genotype (86 patients, p = 0.050), while the decrease-in-function genotype 1080 TT was more likely to experience DCI relative to those with 1080 CC and CT genotypes (84 patients, p = 0.042). Serum homocysteine levels did not correlate with the extent of either angiographic vasospasm or DCI in this analysis. Conclusions. Polymorphisms of the CBS gene that impart gain-of-function may be associated with a reduced risk of DCI after aSAH, independent of serum homocysteine. Signaling through H2S may mediate protection from DCI following aSAH through a mechanism that does not involve macrovascular vasodilation.

Original languageEnglish (US)
Pages (from-to)101-107
Number of pages7
JournalJournal of neurosurgery
Volume115
Issue number1
DOIs
StatePublished - Jul 1 2011

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Cystathionine
Subarachnoid Hemorrhage
Brain Ischemia
Homocysteine
Genotype
Serum
Genes
Hydrogen Sulfide
Cheek
Patient Admission
Incidence
Vasodilator Agents
Ion Channels
Vasodilation
Multivariate Analysis
Databases
Hypertension
Polymerase Chain Reaction
DNA
Brain

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Grobelny, Bartosz T. ; Ducruet, Andrew F. ; Derosa, Peter A. ; Kotchetkov, Ivan S. ; Zacharia, Brad E. ; Hickman, Zachary L. ; Fernandez, Luis ; Narula, Reshma ; Claassen, Jan ; Lee, Kiwon ; Badjatia, Neeraj ; Mayer, Stephan A. ; Connolly, E. Sander. / Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage : Clinical article. In: Journal of neurosurgery. 2011 ; Vol. 115, No. 1. pp. 101-107.
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title = "Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage: Clinical article",
abstract = "Object. Cystathionine β-synthase (CBS) is an enzyme that metabolizes homocysteine to form H2S in the brain. Hydrogen sulfide functions as a vasodilator as well as a regulator of neuronal ion channels and multiple intracellular signaling pathways. Given the myriad effects of H2S, the authors hypothesized that patients possessing gain-of-function polymorphisms of the CBS gene will experience a decreased incidence of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). Methods. Patients were enrolled in a prospective observational database of aSAH outcomes. DNA was extracted from buccal swabs and sequenced for 3 functional polymorphisms of the CBS gene (699C→T, 844ins68, and 1080C→T) by polymerase chain reaction. Serum homocysteine levels (mmol/L) were assayed. Multivariate analysis was used to determine the relationship between CBS genotype and occurrence of both angiographic vasospasm and DCI. Results. There were 87 patients included in the study. None of the polymorphisms investigated were significantly associated with the incidence of angiographic vasospasm. However, after controlling for admission hypertension, patients with the gain-of-function 844 WT/ins genotypes were less likely to experience DCI relative to those with the 844 WT/WT genotype (86 patients, p = 0.050), while the decrease-in-function genotype 1080 TT was more likely to experience DCI relative to those with 1080 CC and CT genotypes (84 patients, p = 0.042). Serum homocysteine levels did not correlate with the extent of either angiographic vasospasm or DCI in this analysis. Conclusions. Polymorphisms of the CBS gene that impart gain-of-function may be associated with a reduced risk of DCI after aSAH, independent of serum homocysteine. Signaling through H2S may mediate protection from DCI following aSAH through a mechanism that does not involve macrovascular vasodilation.",
author = "Grobelny, {Bartosz T.} and Ducruet, {Andrew F.} and Derosa, {Peter A.} and Kotchetkov, {Ivan S.} and Zacharia, {Brad E.} and Hickman, {Zachary L.} and Luis Fernandez and Reshma Narula and Jan Claassen and Kiwon Lee and Neeraj Badjatia and Mayer, {Stephan A.} and Connolly, {E. Sander}",
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Grobelny, BT, Ducruet, AF, Derosa, PA, Kotchetkov, IS, Zacharia, BE, Hickman, ZL, Fernandez, L, Narula, R, Claassen, J, Lee, K, Badjatia, N, Mayer, SA & Connolly, ES 2011, 'Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage: Clinical article', Journal of neurosurgery, vol. 115, no. 1, pp. 101-107. https://doi.org/10.3171/2011.2.JNS101414

Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage : Clinical article. / Grobelny, Bartosz T.; Ducruet, Andrew F.; Derosa, Peter A.; Kotchetkov, Ivan S.; Zacharia, Brad E.; Hickman, Zachary L.; Fernandez, Luis; Narula, Reshma; Claassen, Jan; Lee, Kiwon; Badjatia, Neeraj; Mayer, Stephan A.; Connolly, E. Sander.

In: Journal of neurosurgery, Vol. 115, No. 1, 01.07.2011, p. 101-107.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage

T2 - Clinical article

AU - Grobelny, Bartosz T.

AU - Ducruet, Andrew F.

AU - Derosa, Peter A.

AU - Kotchetkov, Ivan S.

AU - Zacharia, Brad E.

AU - Hickman, Zachary L.

AU - Fernandez, Luis

AU - Narula, Reshma

AU - Claassen, Jan

AU - Lee, Kiwon

AU - Badjatia, Neeraj

AU - Mayer, Stephan A.

AU - Connolly, E. Sander

PY - 2011/7/1

Y1 - 2011/7/1

N2 - Object. Cystathionine β-synthase (CBS) is an enzyme that metabolizes homocysteine to form H2S in the brain. Hydrogen sulfide functions as a vasodilator as well as a regulator of neuronal ion channels and multiple intracellular signaling pathways. Given the myriad effects of H2S, the authors hypothesized that patients possessing gain-of-function polymorphisms of the CBS gene will experience a decreased incidence of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). Methods. Patients were enrolled in a prospective observational database of aSAH outcomes. DNA was extracted from buccal swabs and sequenced for 3 functional polymorphisms of the CBS gene (699C→T, 844ins68, and 1080C→T) by polymerase chain reaction. Serum homocysteine levels (mmol/L) were assayed. Multivariate analysis was used to determine the relationship between CBS genotype and occurrence of both angiographic vasospasm and DCI. Results. There were 87 patients included in the study. None of the polymorphisms investigated were significantly associated with the incidence of angiographic vasospasm. However, after controlling for admission hypertension, patients with the gain-of-function 844 WT/ins genotypes were less likely to experience DCI relative to those with the 844 WT/WT genotype (86 patients, p = 0.050), while the decrease-in-function genotype 1080 TT was more likely to experience DCI relative to those with 1080 CC and CT genotypes (84 patients, p = 0.042). Serum homocysteine levels did not correlate with the extent of either angiographic vasospasm or DCI in this analysis. Conclusions. Polymorphisms of the CBS gene that impart gain-of-function may be associated with a reduced risk of DCI after aSAH, independent of serum homocysteine. Signaling through H2S may mediate protection from DCI following aSAH through a mechanism that does not involve macrovascular vasodilation.

AB - Object. Cystathionine β-synthase (CBS) is an enzyme that metabolizes homocysteine to form H2S in the brain. Hydrogen sulfide functions as a vasodilator as well as a regulator of neuronal ion channels and multiple intracellular signaling pathways. Given the myriad effects of H2S, the authors hypothesized that patients possessing gain-of-function polymorphisms of the CBS gene will experience a decreased incidence of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). Methods. Patients were enrolled in a prospective observational database of aSAH outcomes. DNA was extracted from buccal swabs and sequenced for 3 functional polymorphisms of the CBS gene (699C→T, 844ins68, and 1080C→T) by polymerase chain reaction. Serum homocysteine levels (mmol/L) were assayed. Multivariate analysis was used to determine the relationship between CBS genotype and occurrence of both angiographic vasospasm and DCI. Results. There were 87 patients included in the study. None of the polymorphisms investigated were significantly associated with the incidence of angiographic vasospasm. However, after controlling for admission hypertension, patients with the gain-of-function 844 WT/ins genotypes were less likely to experience DCI relative to those with the 844 WT/WT genotype (86 patients, p = 0.050), while the decrease-in-function genotype 1080 TT was more likely to experience DCI relative to those with 1080 CC and CT genotypes (84 patients, p = 0.042). Serum homocysteine levels did not correlate with the extent of either angiographic vasospasm or DCI in this analysis. Conclusions. Polymorphisms of the CBS gene that impart gain-of-function may be associated with a reduced risk of DCI after aSAH, independent of serum homocysteine. Signaling through H2S may mediate protection from DCI following aSAH through a mechanism that does not involve macrovascular vasodilation.

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