title: Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage.
abstract: OBJECTIVE
  Cystathionine β-synthase (CBS) is an enzyme that metabolizes homocysteine to form H(2)S 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 H(2)S, 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 (μmol/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 H(2)S may mediate protection from DCI following aSAH through a mechanism that does not involve macrovascular vasodilation.
authors.affiliation: Department of Neurosurgery, New York University Medical Center, New York, New York, USA. bartosz.grobelny@nyumc.org
authors.forename: Bartosz T
authors.initials: BT
authors.lastname: Grobelny
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ducruet
authors.forename: Peter A
authors.initials: PA
authors.lastname: DeRosa
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Kotchetkov
authors.forename: Brad E
authors.initials: BE
authors.lastname: Zacharia
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Hickman
authors.forename: Luis
authors.initials: L
authors.lastname: Fernandez
authors.forename: Reshma
authors.initials: R
authors.lastname: Narula
authors.forename: Jan
authors.initials: J
authors.lastname: Claassen
authors.forename: Kiwon
authors.initials: K
authors.lastname: Lee
authors.forename: Neeraj
authors.initials: N
authors.lastname: Badjatia
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Mayer
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
mesh_terms: D000368:Aged; D002545:Brain Ischemia / Q000209:etiology* / Q000235:genetics*; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D013997:Time Factors; D020301:Vasospasm, Intracranial / Q000235:genetics
chemical_list: D006710:Homocysteine; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide