title: Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations.
abstract: OBJECTIVE
  Identification of single-nucleotide polymorphisms (SNPs) associated with increased risk of new intracranial hemorrhage (ICH) after brain arteriovenous malformation (BAVM) diagnosis would facilitate risk stratification and identify potential targets for therapeutic intervention.
  
  
  METHODS
  Patients with BAVM were longitudinally followed. Primary outcome was new ICH after diagnosis; censoring events were last follow-up or any BAVM treatment. We genotyped 4 promoter SNPs in 2 inflammatory cytokine genes: interleukin-6 (IL-6-174G>C; IL-6-572G>C) and tumor necrosis factor-alpha (TNF-alpha-238G>A; TNF-alpha-308G>A). Association of genotype with risk of new ICH was screened using chi2; SNPs associated with new ICH were further characterized using Cox proportional hazards.
  
  
  RESULTS
  We genotyped 280 patients (50% female; 59% white, mean+/-SD age at diagnosis 37+/-17 years; 40% presenting with ICH). TNF-alpha-238G>A was associated with increased risk of new ICH after diagnosis (chi2; P=0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF-alpha-238 AG genotype (hazard ratio, 4.01; P=0.015). No other SNP was found to be associated with new ICH.
  
  
  CONCLUSIONS
  A TNF-alpha SNP was associated with increased risk of new ICH in the natural course of BAVMs. The role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage merits further study.
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, California, USA.
authors.forename: Achal S
authors.initials: AS
authors.lastname: Achrol
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCulloch
authors.forename: K Y Trudy
authors.initials: KY
authors.lastname: Poon
authors.forename: Connie
authors.initials: C
authors.lastname: Ha
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Zaroff
authors.forename: S Claiborne
authors.initials: SC
authors.lastname: Johnston
authors.forename: Chanhung
authors.initials: C
authors.lastname: Lee
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lawton
authors.forename: Stephen
authors.initials: S
authors.lastname: Sidney
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: William L
authors.initials: WL
authors.lastname: Young
mesh_terms: D000328:Adult; D001165:Arteriovenous Malformations / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006470:Hemorrhage / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012306:Risk; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha