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

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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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All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Grobelny, B. T., Ducruet, A. F., Derosa, P. A., Kotchetkov, I. S., Zacharia, B. E., Hickman, Z. L., Fernandez, L., Narula, R., Claassen, J., Lee, K., Badjatia, N., Mayer, S. A., & Connolly, E. S. (2011). Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage: Clinical article. Journal of neurosurgery, 115(1), 101-107. https://doi.org/10.3171/2011.2.JNS101414